Tetrazine bicyclic compounds

ABSTRACT

Corticotropin releasing factor (CRF) antagonists of formula I or II:                    
     and their use in treating anxiety, depression, and other psychiatric, neurological disorders as well as treatment of immunological, cardiovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological disturbance and stress.

This application is a continuation-in-part of U.S. Ser. No. 08/899,242filed Jul. 23, 1997, which-in-turn is a continuation of U.S. ProvisionalAplication No. 60/023,290 filed Jul. 24, 1997.

FIELD OF THE INVENTION

This invention relates a treatment of psychiatric disorders andneurological diseases including major depression, anxiety-relateddisorders, post-traumatic stress disorder, supranuclear palsy andfeeding disorders as well as treatment of immunological, cardiovascularor heart-related diseases and colonic hypersensitivity associated withpsychopathological disturbance and stress, by administration of certain[1,5-a]-pyrazolo-1,3,5-triazines,[1,5-a]-1,2,3-triazolo-1,3,5-triazines, [1,5-a]-pyrazolo-pyrimidines and[1,5-a]-1,2,3-triazolo-pyrimidines.

BACKGROUND OF THE INVENTION

Corticotropin releasing factor (herein referred to as CRF), a 41 aminoacid peptide, is the primary physiological regulator ofproopiomelanocortin(POMC)—derived peptide secretion from the anteriorpituitary gland [J. Rivier et al., Proc. Nat. Acad. Sci. (USA) 80:4851(1983); W. Vale et al., Science 213:1394 (1981)]. In addition to itsendocrine role at the pituitary gland, immunohistochemical localizationof CRF has demonstrated that the hormone has a broad extrahypothalamicdistribution in the central nervous system and produces a wide spectrumof autonomic, electrophysiological and behavioral effects consistentwith a neurotransmitter or neuromodulator role in brain [W. Vale et al.,Rec. Prog. Horm. Res. 39:245 (1983); G. F. Koob, Persp. Behav. Med. 2:39(1985); E. B. De Souza et al., J. Neurosci. 5:3189 (1985)]. There isalso evidence that CRF plays a significant role in integrating theresponse of the immune system to physiological, psychological, andimmunological stressors [J. E. Blalock, Physiological Reviews 69:1(1989); J. E. Morley, Life Sci. 41:527 (1987)].

Clinical data provide evidence that CRF has a role in psychiatricdisorders and neurological diseases including depression,anxiety-related disorders and feeding disorders. A role for CRF has alsobeen postulated in the etiology and pathophysiology of Alzheimer'sdisease, Parkinson's disease, Huntington's disease, progressivesupranuclear palsy and amyotrophic lateral sclerosis as they relate tothe dysfunction of CRF neurons in the central nervous system [for reviewsee E. B. De Souza, Hosp. Practice 23:59 (1988)].

In affective disorder, or major depression, the concentration of CRF issignificantly increased in the cerebral spinal fluid (CSF) of drug-freeindividuals [C. B. Nemeroff et al., Science 226:1342 (1984); C. M. Bankiet al., Am. J. Psychiatry 144:873 (1987); R. D. France et al., Biol.Psychiatry 28:86 (1988); M. Arato et al., Biol Psychiatry 25:355(1989)]. Furthermore, the density of CRF receptors is significantlydecreased in the frontal cortex of suicide victims, consistent with ahypersecretion of CRF [C. B. Nemeroff et al., Arch. Gen. Psychiatry45:577 (1988)]. In addition, there is a blunted adrenocorticotropin(ACTH) response to CRF (i.v. administered) observed in depressedpatients [P. W. Gold et al., Am J. Psychiatry 141:619 (1984); F.Holsboer et al., Psychoneuroendocrinology 9:147 (1984); P. W. Gold etal., New Eng. J. Med. 314:1129 (1986)]. Preclinical studies in rats andnon-human primates provide additional support for the hypothesis thathypersecretion of CRF may be involved in the symptoms seen in humandepression [R. M. Sapolsky, Arch. Gen. Psychiatry 46:1047 (1989)]. Thereis preliminary evidence that tricyclic antidepressants can alter CRFlevels and thus modulate the numbers of CRF receptors in brain[Grigoriadis et al., Neuropsychopharmacology 2:53 (1989)].

There has also been a role postulated for CRF in the etiology ofanxiety-related disorders. CRF produces anxiogenic effects in animalsand interactions between benzodiazepine/non-benzodiazepine anxiolyticsand CRF have been demonstrated in a variety of behavioral anxiety models[D. R. Britton et al., Life Sci. 31:363 (1982); C. W. Berridge and A. J.Dunn Regul. Peptides 16:83 (1986)]. Preliminary studies using theputative CRF receptor antagonist a-helical ovine CRF (9-41) in a varietyof behavioral paradigms demonstrate that the antagonist produces“anxiolytic-like” effects that are qualitatively similar to thebenzodiazepines [C. W. Berridge and A. J. Dunn Horm. Behav. 21:393(1987), Brain Research Reviews 15:71 (1990)]. Neurochemical, endocrineand receptor binding studies have all demonstrated interactions betweenCRF and benzodiazepine anxiolytics providing further evidence for theinvolvement of CRF in these disorders. Chlordiazepoxide attenuates the“anxiogenic” effects of CRF in both the conflict test [K. T. Britton etal., Psychopharmacology 86:170 (1985); K. T. Britton et al.,Psychopharmacology 94:306 (1988)] and in the acoustic startle test [N.R. Swerdlow et al., Psychopharmacology 88:147 (1986)] in rats. Thebenzodiazepine receptor antagonist (Ro15-1788), which was withoutbehavioral activity alone in the operant conflict test, reversed theeffects of CRF in a dose-dependent manner while the benzodiazepineinverse agonist (FG7142) enhanced the actions of CRF [K. T. Britton etal., Psychopharmacology 94:306 (1988)].

The mechanisms and sites of action through which the standardanxiolytics and antidepressants produce their therapeutic effects remainto be elucidated. It has been hypothesized however, that they areinvolved in the suppression of the CRF hypersecretion that is observedin these disorders. Of particular interest is that preliminary studiesexamining the effects of a CRF receptor antagonist (α-helical CRF₉₋₄₁)in a variety of behavioral paradigms have demonstrated that the CRFantagonist produces “anxiolytic-like” effects qualitatively similar tothe benzodiazepines [for review see G. F. Koob and K. T. Britton, In:Corticotropin-Releasing Factor: Basic and Clinical Studies of aNeuropeptide, E. B. De Souza and C. B. Nemeroff eds., CRC Press p221(1990)].

Several publications describe corticotropin releasing factor antagonistcompounds and their use to treat psychiatric disorders and neurologicaldiseases. Examples of such publications include DuPont Merck PCTapplication U.S. Ser. No. 94/11050, Pfizer WO 95/33750, Pfizer WO95/34563, Pfizer WO 95/33727 and Pfizer EP 0778 277 A1.

Insofar as is known, [1,5-a]-pyrazolo-1,3,5-triazines,[1,5-a]-1,2,3-triazolo-1,3,5-triazines, [1,5-a]-pyrazolo-pyrimidines and[1,5-a]-1,2,3-triazolo-pyrimidines, have not been previously reported ascorticotropin releasing factor antagonist compounds useful in thetreatment of psychiatric disorders and neurological diseases. However,there have been publications which teach some of these compounds forother uses.

For instance, EP 0 269 859 (Ostuka, 1988) discloses pyrazolotriazinecompounds of the formula

where R¹ is OH or alkanoyl, R² is H, OH, or SH, and R³ is an unsaturatedheterocyclic group, naphthyl or substituted phenyl, and states that thecompounds have xanthine oxidase inhibitory activity and are useful fortreatment of gout.

EP 0 594 149 (Ostuka, 1994) discloses pyrazolotriazine andpyrazolopyrimidine compounds of the formula

where A is CH or N, R⁰ and R³ are H or alkyl, and R¹ and R² are H,alkyl, alkoxyl, alkylthio, nitro, etc., and states that the compoundsinhibit androgen and are useful in treatment of benign prostatichypertrophy and prostatic carcinoma.

U.S. Pat. No. 3,910,907 (ICI, 1975) discloses pyrazolotriazines of theformula:

where R1 is CH₃, C₂H₅ or C₆H₅, X is H, C₆H₅, m-CH₃C₆H₄, CN, COOEt, Cl, Ior Br, Y is H, C₆H₅, o-CH₃C₆H₄, or p-CH₃C₆H₄, and Z is OH, H, CH₃, C₂H₅,C₆H₅, n-C₃H₇, i-C₃H₇, SH, SCH₃, NHC₄H₉, or N(C₂H₅)₂, and states that thecompounds are c-AMP phosphodiesterase inhibitors useful asbronchodilators.

U.S. Pat. No. 3,995,039 discloses pyrazolotriazines of the formula:

where R¹ is H or alkyl, R² is H or alkyl, R³ is H, alkyl, alkanoyl,carbamoyl, or lower alkylcarbamoyl, and R is pyridyl, pyrimidinyl, orpyrazinyl, and states that the compounds are useful as bronchodilators.

U.S. Pat. No. 5,137,887 discloses pyrazolotriazines of the formula

where R is lower alkoxy, and teaches that the compounds are xanthineoxidase inhibitors and are useful for treatment of gout.

U.S. Pat. No. 4,892,576 discloses pyrazolotriazines of the formula

where X is O or S, Ar is a phenyl, naphthyl, pyridyl or thienyl group,R₆-R₈ are H, alkyl, etc., and R₉ is H, alkyl, phenyl, etc. The patentstates that the compounds are useful as herbicides and plant growthregulants.

U.S. Pat. No. 5,484,760 and WO 92/10098 discloses herbicidalcompositions containing, among other things, a herbicidal compound ofthe formula

where A can be N, B can be CR₃, R₃ can be phenyl or substituted phenyl,etc., R is —N(R₄)SO₂R₅ or —SO₂N(R₆)R₇ and R₁ and R₂ can be takentogether to form

where X, Y and Z are H, alkyl, acyl, etc. and D is O or S.

U.S. Pat. No. 3,910,907 and Senga et al., J. Med. Chem., 1982, 25,243-249, disclose triazolotriazines cAMP phosphodiesterase inhibitors ofthe formula

where Z is H, OH, CH₃, C₂H₅, C₆H₅, n-C₃H₇, iso-C₃H₇, SH, SCH₃,NH(n-C₄H₉), or N(C₂H₅)₂, R is H or CH₃, and R₁ is CH₃ or C₂H₅. Thereference lists eight therapeutic areas where inhibitors of cAMPphosphodiesterase could have utility: asthma, diabetes mellitus, femalefertility control, male infertility, psoriasis, thrombosis, anxiety, andhypertension.

WO95/35298 (Otsuka, 1995) discloses pyrazolopyrimidines and states thatthey are useful as analgesics. The compounds are represented by theformula

where Q is carbonyl or sulfonyl, n is 0 or 1, A is a single bond,alkylene or alkenylene, R¹ is H, alkyl, etc., R² is naphthyl,cycloalkyl, heteroaryl, substituted phenyl or phenoxy, R³ is H, alkyl orphenyl, R⁴ is H, alkyl, alkoxycarbonyl, phenylalkyl, optionallyphenylthio-substituted phenyl, or halogen, R⁵ and R⁶ are H or alkyl.

EP 0 591 528 (Otsuka, 1991) discloses anti-inflammatory use ofpyrazolopyrimidines represented by the formula

where R₁, R₂, R₃ and R₄ are H, carboxyl, alkoxycarbonyl, optionallysubstituted alkyl, cycloalkyl, or phenyl, R₅ is SR₆ or NR₇R₈, R₆ ispyridyl or optionally substituted phenyl, and R₇ and R₈ are H oroptionally substituted phenyl.

Springer et al, J. Med. Chem., 1976, vol. 19, no. 2, 291-296 andSpringer U.S. Pat. Nos. 4,021,556 and 3,920,652 disclosepyrazolopyrimidines of the formula

where R can be phenyl, substituted phenyl or pyridyl, and their use totreat gout, based on their ability to inhibit xanthine oxidase.

Joshi et al., J. Prakt. Chemie, 321, 2, 1979, 341-344, disclosescompounds of the formula

where R¹ is CF₃, C₂F₅, or C₆H₄F, and R² is CH₃, C₂H₅, CF₃, or C₆H₄F.

Maquestiau et al., Bull. Soc. Belg., vol.101, no. 2, 1992, pages 131-136discloses a pyrazolo[1,5-a]pyrimidine of the formula

Ibrahim et al., Arch. Pharm. (weinheim) 320, 487-491 (1987) disclosespyrazolo[1,5-a]pyrimidines of the formula

where R is NH2 or OH and Ar is 4-phenyl-3-cyano-2-aminopyrid-2-yl.

Other references which disclose azolopyrimidines inclued EP 0 511 528(Otsuka, 1992), U.S. Pat. No. 4,997,940 (Dow, 1991), EP 0 374 448(Nissan, 1990), U.S. Pat. No. 4,621,556 (ICN, 1997), EP 0 531 901(Fujisawa, 1993), U.S. Pat. No. 4,567,263 (BASF, 1986), EP 0 662 477(Isagro, 1995), U.S. Pat. No. DE 4 243 279 (Bayer, 1994), U.S. Pat. No.5,397,774 (Upjohn, 1995), EP 0 521 622 (Upjohn, 1993), WO 94/109017(Upjohn, 1994), J. Med. Chem., 24, 610-613 ( 1981), and J. Het. Chem.,22, 601 ( 1985).

SUMMARY OF THE INVENTION

In accordance with one aspect, the present invention provides novelcompounds, pharmaceutical compositions and methods which may be used inthe treatment of affective disorder, anxiety, depression, irritablebowel syndrome, post-traumatic stress disorder, supranuclear palsy,immune suppression, Alzheimer's disease, gastrointestinal disease,anorexia nervosa or other feeding disorder, drug or alcohol withdrawalsymptoms, drug addiction, inflammatory disorder, fertility problems,disorders, the treatment of which can be effected or facilitated byantagonizing CRF, including but not limited to disorders induced orfacilitated by CRF, or a disorder selected from inflammatory disorderssuch as rheumatoid arthritis and osteoarthritis, pain, asthma, psoriasisand allergies; generalized anxiety disorder; panic, phobias,obsessive-compulsive disorder; post-traumatic stress disorder; sleepdisorders induced by stress; pain perception such as fibromyalgia; mooddisorders such as depression, including major depression, single episodedepression, recurrent depression, child abuse induced depression, andpostpartum depression; dysthemia; bipolar disorders; cyclothymia;fatigue syndrome; stress-induced headache; cancer, humanimmunodeficiency virus (HIV) infections; neurodegenerative diseases suchas Alzheimer's disease, Parkinson's disease and Huntington's disease;gastrointestinal diseases such as ulcers, irritable bowel syndrome,Crohn's disease, spastic colon, diarrhea, and post operative ilius andcolonic hypersensitivity associated by psychopathological disturbancesor stress; eating disorders such as anorexia and bulimia nervosa;hemorrhagic stress; stress-induced psychotic episodes; euthyroid sicksyndrome; syndrome of inappropriate antidiarrhetic hormone (ADH);obesity; infertility; head traumas; spinal cord trauma; ischemicneuronal damage (e.g., cerebral ischemia such as cerebral hippocampalischemia); excitotoxic neuronal damage; epilepsy; cardiovascular andhear related disorders including hypertension, tachycardia andcongestive heart failure; stroke; immune dysfunctions including stressinduced immune dysfunctions (e.g., stress induced fevers, porcine stresssyndrome, bovine shipping fever, equine paroxysmal fibrillation, anddysfunctions induced by confinement in chickens, sheering stress insheep or human-animal interaction related stress in dogs); muscularspasms; urinary incontinence; senile dementia of the Alzheimer's type;multiinfarct dementia; amyotrophic lateral sclerosis; chemicaldependencies and addictions (e.g., dependencies on alcohol, cocaine,heroin, benzodiazepines, or other drugs); drug and alcohol withdrawalsymptoms; osteoporosis; psychosocial dwarfism and hypoglycemia in amammal.

The present invention provides novel compounds which bind tocorticotropin releasing factor receptors, thereby altering theanxiogenic effects of CRF secretion. The compounds of the presentinvention are useful for the treatment of psychiatric disorders andneurological diseases, anxiety-related disorders, post-traumatic stressdisorder, supranuclear palsy and feeding disorders as well as treatmentof immunological, cardiovascular or heart-related diseases and colonichypersensitivity associated with psychopathological disturbance andstress in a mammal.

According to another aspect, the present invention provides novelcompounds of Formulae (1) and (2) (described below) which are useful asantagonists of the corticotropin releasing factor. The compounds of thepresent invention exhibit activity as corticotropin releasing factorantagonists and appear to suppress CRF hypersecretion. The presentinvention also includes pharmaceutical compositions containing suchcompounds of Formulae (1) and (2), and methods of using such compoundsfor the suppression of CRF hypersecretion, and/or for the treatment ofanxiogenic disorders.

According to yet another aspect of the invention, the compounds providedby this invention (and especially labelled compounds of this invention)are also useful as standards and reagents in determining the ability ofa potential pharmaceutical to bind to the CRF receptor.

DETAILED DESCRIPTION OF INVENTION

[1] The present invention comprises a method of treating affectivedisorder, anxiety, depression, headache, irritable bowel syndrome,post-traumatic stress disorder, supranuclear palsy, immune suppression,Alzheimer's disease, gastrointestinal diseases, anorexia nervosa orother feeding disorder, drug addiction, drug or alcohol withdrawalsymptoms, inflammatory diseases, cardiovascular or heart-relateddiseases, fertility problems, human immunodeficiency virus infections,hemorrhagic stress, obesity, infertility, head and spinal cord traumas,epilepsy, stroke, ulcers, amyotrophic lateral sclerosis, hypoglycemia ora disorder the treatment of which can be effected or facilitated byantagonizing CRF, including but not limited to disorders induced orfacilitated by CRF, in mammals comprising administering to the mammal atherapeutically effective amount of a compound of Formulae (1) or (2):

and isomers thereof, stereoisomeric forms thereof, or mixtures ofstereoisomeric forms thereof, and pharmaceutically acceptable salt orpro-drug forms thereof, wherein:

A is N or CR;

Z is N or CR²;

Ar is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl,furanyl, thienyl, benzothienyl, benzofuranyl, 2,3-dihydrobenzofuranyl,2,3-dihydrobenzothienyl, indanyl, 1,2-benzopyranyl,3,4-dihydro-1,2-benzopyranyl, tetralinyl, each Ar optionally substitutedwith 1 to 5 R⁴ groups and each Ar is attached to an unsaturated carbonatom;

R is independently selected at each occurrence from H, C₁-C₄ alkyl,C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,halo, CN, C₁-C₄ haloalkyl;

R¹ is independently selected at each occurrence from H, C₁-C₄ alkyl,C₂-C₄ alkenyl, C₂-C₄ alkynyl, halo, CN, C₁-C₄ haloalkyl, C₁-C₁₂hydroxyalkyl, C₂-C₁₂ alkoxyalkyl, C₂-C₁₀ cyanoalkyl, C₃-C₆ cycloalkyl,C₄-C_(l0) cycloalkylalkyl, NR⁹R¹⁰, C₁-C₄ alkyl-NR⁹R¹⁰, NR⁹COR¹⁰, OR¹¹,SH or S(O)_(n)R¹²;

R² is selected from H, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆cycloalkyl, C₄-C₁₀ cycloalkylalkyl, C₁-C₄ hydroxyalkyl, halo, CN,—NR⁶R⁷, NR⁹COR¹⁰, —NR⁶S(O)_(n)R⁷, S(O)_(n)NR⁶R⁷, C₁-C₄ haloalkyl, —OR⁷,SH or —S(O)_(n)R¹²;

R³ is selected from:

H, OR⁷, SH, S(O)_(n)R¹³, COR⁷, CO₂R⁷, OC(O)R¹³, NR⁸COR⁷, N(COR⁷)₂,NR⁸CONR⁶R⁷, NR⁸CO₂R¹³, NR⁶R⁷, NR^(6a)R^(7a), N(OR⁷)R⁶, CONR⁶R⁷, aryl,heteroaryl and heterocyclyl, or

C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈cycloalkenyl, C₄-C₁₂ cycloalkylalkyl or C₆-C₁₀ cycloalkenylalkyl, eachoptionally substituted with 1 to 3 substituents independently selectedat each occurrence from C₁-C₆ alkyl, C₃-C₆ cycloalkyl, halo, C₁-C₄haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³,NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl,heteroaryl and heterocyclyl;

R⁴ is independently selected at each occurrence from:

C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₆ cycloalkyl, C₄-C₁₂cycloalkylalkyl, NO₂, halo, CN, C₁-C₄ haloalkyl, NR⁶R⁷, NR⁸COR⁷,NR⁸CO₂R⁷, COR⁷, OR⁷, CONR⁶R⁷, CO(NOR⁹)R⁷, CO₂R⁷, or S(O)_(n)R⁷, whereeach such C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₆ cycloalkyland C₄-C₁₂ cycloalkylalkyl are optionally substituted with 1 to 3substituents independently selected at each occurrence from C₁-C₄ alkyl,NO₂, halo, CN, NR⁶R⁷, NR⁸COR⁷, NR⁸CO₂R⁷, COR⁷OR⁷, CONR⁶R⁷, CO₂R⁷,CO(NOR⁹)R⁷, or S(O)_(n)R⁷;

R⁶ and R⁷, R^(6a) and R^(7a) are independently selected at eachoccurrence from:

H,

C₁-C₁₀ alkyl, C₃-C₁₀ alkenyl, C₃-C₁₀ alkynyl, C₁-C₁₀ haloalkyl with 1-10halogens, C₂-C₈ alkoxyalkyl, C₃-C₆cycloalkyl, C₄-C₁₂ cycloalkylalkyl,C₅-C₁₀ cycloalkenyl, or C₆-C₁₄ cycloalkenylalkyl, each optionallysubstituted with 1 to 3 substituents independently selected at eachoccurrence from C₁-C₆ alkyl, C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl,cyano, OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵,N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroarylor heterocyclyl,

aryl, aryl(C₁-C₄ alkyl), heteroaryl, heteroaryl(C₁-C₄ alkyl),heterocyclyl or heterocyclyl(C₁-C₄ alkyl);

alternatively, NR⁶R⁷ and NR^(6a)R^(7a) are independently piperidine,pyrrolidine, piperazine, N-methylpiperazine, morpholine orthiomorpholine, each optionally substituted with 1-3 C₁-C₄ alkyl groups;

R⁸ is independently selected at each occurrence from H or C₁-C₄ alkyl;

R⁹ and R¹⁰ are independently selected at each occurrence from H, C₁-C₄alkyl, or C₃-C₆ cycloalkyl;

R¹¹ is selected from H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₃-C₆cycloalkyl;

R¹² is C₁-C₄ alkyl or C₁-C₄ haloalkyl;

R¹³ is selected from C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₂-C₈ alkoxyalkyl,C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl, aryl, aryl(C₁-C₄ alkyl)-,heteroaryl or heteroaryl(C₁-C₄ alkyl)-;

R¹⁴ is selected from C₁-C₁₀ alkyl, C₃-C₁₀ alkenyl, C₃-C₁₀ alkynyl, C₃-C₈cycloalkyl, or C₄-C₁₂ cycloalkylalkyl, each optionally substituted with1 to 3 substituents independently selected at each occurrence from C₁-C₆alkyl, C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl, cyano, OR¹⁵, SH,S(O)_(n)R¹⁵, COR¹⁵, CO₂R¹⁵, OC(O)R¹⁵, NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵,NR⁸CO₂R¹⁵, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, and C₁-C₆ alkylthio, C₁-C₆ alkylsulfinyland C₁-C₆ alkylsulfonyl;

R¹⁵ and R¹⁶ are independently selected at each occurrence from H, C₁-C₆alkyl, C₃-C₁₀ cycloalkyl, C₄-C₁₆ cycloalkylalkyl, except that forS(O)_(n)R¹⁵, R¹⁵ cannot be H;

aryl is phenyl or naphthyl, each optionally substituted with 1 to 5substituents independently selected at each occurrence from C₁-C₆ alkyl,C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹⁵,COR¹⁵, CO₂R¹⁵, OC(O)R¹⁵, NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹⁵,NR¹⁶R¹⁵, and CONR¹⁶R¹⁵;

heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, pyranyl,quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl,pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl,isoxazolyl, pyrazolyl, 2,3-dihydrobenzothienyl or2,3-dihydrobenzofuranyl, each being optionally substituted with 1 to 5substituents independently selected at each occurrence from C₁-C₆ alkyl,C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹⁵,—COR¹⁵, CO₂R¹⁵, OC(O)R¹⁵, NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹⁵,NR¹⁶R¹⁵, and CONR¹⁶R¹⁵;

heterocyclyl is saturated or partially saturated heteroaryl, optionallysubstituted with 1 to 5 substituents independently selected at eachoccurrence from C₁-C₆ alkyl, C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl,cyano, OR¹⁵, SH, S(O)_(n)R¹⁵, COR¹⁵, CO₂R¹⁵, OC(O)R¹⁵, NR⁸COR¹⁵,N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹⁵, NR¹⁵R¹⁶, and CONR¹⁶R¹⁵;

n is independently at each occurrence 0, 1 or 2,

[2] Preferred methods of the present invention are methods in wherein inthe compound of Formulae (1) or (2), Ar is phenyl, pyridyl or2,3-dihydrobenzofuranyl, each optionally substituted with 1 to 4 R⁴substituents.

[3] Further preferred methods of the above invention are methodswherein, in the compound of Formulae (1) or (2), A is N, Z is CR², Ar is2,4-dichlorophenyl, 2,4-dimethylphenyl or 2,4,6-trimethylphenyl, R¹ andR² are CH₃, and R³ is NR^(6a)R^(7a).

[4] The present invention comprises compounds of Formulae (1) or (2):

and isomers thereof, stereoisomeric forms thereof, or mixtures ofstereoisomeric forms thereof, and pharmaceutically acceptable salt orpro-drug forms thereof wherein:

A is N or CR;

Z is N or CR²;

Ar is-selected from phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl,furanyl, thienyl, benzothienyl, benzofuranyl, 2,3-dihydrobenzofuranyl,2,3-dihydrobenzothienyl, indanyl, 1,2-benzopyranyl,3,4-dihydro-1,2-benzopyranyl, tetralinyl, each Ar optionally substitutedwith 1 to 5 R⁴ groups and each Ar is attached to an unsaturated carbonatom;

R is independently selected at each occurrence from H, C₁-C₄ alkyl,C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,halo, CN, C₁-C₄ haloalkyl;

R¹ is independently selected at each occurrence from H, C₁-C₄ alkyl,C₂-C₄ alkenyl, C₂-C₄ alkynyl, halo, CN, C₁-C₄ haloalkyl, C₁-C₁₂hydroxyalkyl, C₂-C₁₂ alkoxyalkyl, C₂-C₁₀ cyanoalkyl, C₃-C₆ cycloalkyl,C₄-C₁₀ cycloalkylalkyl, NR⁹R¹⁰, C₁-C₄ alkyl-NR⁹R¹⁰, NR⁹COR¹⁰, OR¹¹, SHor S(O)_(n)R¹²;

R² is selected from H, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆cycloalkyl, C₄-C₁₀ cycloalkylalkyl, C₁-C₄ hydroxyalkyl, halo, CN,—NR⁶R⁷, NR⁹COR¹⁰, —NR⁶S(O)_(n)R⁷, S(O)_(n)NR⁶R⁷, C₁-C₄ haloalkyl, —OR⁷,SH or —S(O)_(n)R¹²;

R³ is selected from:

H, OR⁷, SH, S(O)_(n)R¹³, COR⁷, CO₂R⁷, OC(O)R¹³, NR⁸COR⁷, N(COR⁷)₂,NR⁸CONR⁶R⁷, NR⁸CO₂R¹³, NR⁶R⁷, NR^(6a)R^(7a), N(OR⁷)R⁶, CONR⁶R⁷, aryl,heteroaryl and heterocyclyl, or

C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈cycloalkenyl, C₄-C₁₂ cycloalkylalkyl or C₆-C₁₀ cycloalkenylalkyl, eachoptionally substituted with 1 to 3 substituents independently selectedat each occurrence from C₁-C₆ alkyl, C₃-C₆ cycloalkyl, halo, C₁-C₄haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³,NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl,heteroaryl and heterocyclyl;

R⁴ is independently selected at each occurrence from: C₁-C₁₀ alkyl,C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₆ cycloalkyl, C₄-C₁₂cycloalkylalkyl, NO₂, halo, CN, C₁-C₄ haloalkyl, NR⁶R⁷, NR⁸COR⁷,NR⁸CO₂R⁷, COR⁷, OR⁷, CONR⁶R⁷, CO(NOR⁹)R⁷, CO₂R⁷, or S(O)_(n)R⁷, whereeach such C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₆ cycloalkyland C₄-C₁₂ cycloalkylalkyl are optionally substituted with 1 to 3substituents independently selected at each occurrence from C₁-C₄ alkyl,NO₂, halo, CN, NR⁶R⁷, NR⁸COR⁷, NR⁸CO₂R⁷, COR⁷ OR⁷, CONR⁶R⁷, CO₂R⁷,CO(NOR⁹)R⁷, or S(O)_(n)R⁷;

R⁶ and R⁷, R^(6a) and R^(7a) are independently selected at eachoccurrence from:

H,

C₁-C₁₀ alkyl, C₃-C₁₀ alkenyl, C₃-C₁₀ alkynyl, C₁-C₁₀ haloalkyl with 1-10halogens, C₂-C₈ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl,C₅-C₁₀ cycloalkenyl, or C₆-C₁₄ cycloalkenylalkyl, each optionallysubstituted with 1 to 3 substituents independently selected at eachoccurrence from C₁-C₆ alkyl, C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl,cyano, OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵,N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroarylor heterocyclyl,

aryl, aryl(C₁-C₄ alkyl), heteroaryl, heteroaryl(C₁-C₄ alkyl),heterocyclyl or heterocyclyl(C₁-C₄ alkyl),

alternatively, NR⁶R⁷ and NR^(6a)R^(7a) are independently piperidine,pyrrolidine, piperazine, N-methylpiperazine, morpholine orthiomorpholine, each optionally substituted with 1-3 C₁-C₄ alkyl groups;

R⁸ is independently selected at each occurrence from H or C₁-C₄ alkyl;

R⁹ and R¹⁰ are independently selected at each occurrence from H, C₁-C₄alkyl, or C₃-C₆ cycloalkyl;

R¹¹ is selected from H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₃-C₆cycloalkyl;

R¹² is C₁-C₄ alkyl or C₁-C₄ haloalkyl;

R¹³ is selected from C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₂-C₈ alkoxyalkyl,C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl, aryl, aryl(C₁-C₄ alkyl)-,heteroaryl or heteroaryl(C₁-C₄ alkyl)-;

R¹⁴ is selected from C₁-C₁₀ alkyl, C₃-C₁₀ alkenyl, C₃-C₁₀ alkynyl, C₃-C₈cycloalkyl, or C₄-C₁₂ cycloalkylalkyl, each optionally substituted with1 to 3 substituents independently selected at each occurrence from C₁-C₆alkyl, C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl, cyano, OR¹⁵, SH,S(O)_(n)R¹⁵, COR¹⁵, CO₂R¹⁵, OC(O)R¹⁵, NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵,NR⁸CO₂R¹⁵, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, and C₁-C₆ alkylthio, C₁-C₆ alkylsulfinyland C₁-C₆ alkylsulfonyl;

R¹⁵ and R¹⁶ are independently selected at each occurrence from H, C₁-C₆alkyl, C₃-C₁₀ cycloalkyl, C₄-C₁₆ cycloalkylalkyl, except that forS(O)_(n)R¹⁵, R¹⁵ cannot be H;

aryl is phenyl or naphthyl, each optionally substituted with 1 to 5substituents independently selected at each occurrence from C₁-C₆ alkyl,C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹⁵,COR¹⁵, CO₂R¹⁵, OC(O)R¹⁵, NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹⁵,NR¹⁶R¹⁵, and CONR¹⁶R¹⁵;

heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, pyranyl,quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl,pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl,isoxazolyl, pyrazolyl, 2,3-dihydrobenzothienyl or2,3-dihydrobenzofuranyl, each being optionally substituted with 1 to 5substituents independently selected at each occurrence from C₁-C₆ alkyl,C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹⁵,—COR¹⁵, CO₂R¹⁵, OC(O)R¹⁵, NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹⁵,NR¹⁶R¹⁵, and CONR¹⁶R¹⁵;

heterocyclyl is saturated or partially saturated heteroaryl, optionallysubstituted with 1 to 5 substituents independently selected at eachoccurrence from C₁-C₆ alkyl, C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl,cyano, OR¹⁵, SH, S(O)_(n)R¹⁵, COR¹⁵, CO₂R¹⁵, OC(O)R¹⁵, NR⁸COR¹⁵,N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹⁵, NR¹⁵R¹⁶, and CONR¹⁶R¹⁵;

n is independently at each occurrence 0, 1 or 2, with the provisos that:

(1) when A is N, Z is CR², R² is H, R³ is —OR⁷ or —OCOR¹³, and R⁷ is H,then R¹ is not H, OH or SH;

(2) when A is N, Z is CR², R¹ is CH₃ or C₂H₅, R² is H, and R³ is OH, H,CH₃, C₂H₅, C₆H₅, n-C₃H₇, i-C₃H₇, SH, SCH₃, NHC₄H₉, or N(C₂H₅)₂, then Aris not phenyl or m-CH₃-phenyl;

(3) when A is N, Z is CR², R² is H, and Ar is pyridyl, pyrimidinyl orpyrazinyl, and R³ is NR^(6a)R^(7a), then R^(6a) and R^(7a) are not H oralkyl;

(4) when A is N, Z is CR², and R² is SO₂NR⁶R⁷, then R³ is not OH or SH;

(5) when A is CR and Z is CR², then R² is not —NR⁶SO₂R⁷ or —SO₂NR⁶R⁷;

(6) when A is N, Z is CR² and R² is —NR⁶SO₂R⁷ or —SO₂NR⁶R⁷, then R³ isnot OH or SH;

(7) when A is N, Z is CR², R¹ is methyl or ethyl, R² is H, and R³ is H,OH, CH₃, C₂H₅, C₆H₅, n-C₃H₇, iso-C₃H₇, SH, SCH₃, NH(n-C₄H₉), orN(C₂H₅)₂, then Ar is not unsubstituted phenyl or m-methylphenyl;

(8) when A is CR, Z is CR², R² is H, phenyl or alkyl, R³ is NR⁸COR⁷ andAr is phenyl or phenyl substituted with phenylthio, then R⁷ is not aryl,aryl(C₁-C₄ alkyl), heteroaryl, heteroaryl(C₁-C₄ alkyl), heterocyclyl orheterocycly(C₁-C₄ alkyl);

(9) when A is CR, Z is CR², R² is H or alkyl, Ar is phenyl, and R³ isSR¹³ or NR^(6a)R^(7a), then R¹³ is not aryl or heteroaryl and R^(6a) andR^(7a) are not H or aryl; or

(10) when A is CH, Z is CR², R¹ is OR¹¹, R² is H, R³ is OR⁷, and R⁷ andR¹¹ are both H, then Ar is not phenyl, p-Br-phenyl, p-Cl-phenyl,p-NHCOCH₃-phenyl, p-CH₃-phenyl, pyridyl or naphthyl;

(11) when A is CH, Z is CR², R² is H, Ar is unsubstituted phenyl, and R³is CH₃, C₂H₅, CF₃ or C₆H₄F, then R₁ is not CF₃ or C₂F₅;

(12) when A is CR, R is H, Z is CR², R² is OH, and R¹ and R³ are H, thenAr is not phenyl;

(13) when A is CR, R is H, Z is CR², R² is OH or NH₂, R¹ and R³ are CH₃,then Ar is not 4-phenyl-3-cyano-2-aminopyrid-2-yl.

[5] Preferred compounds of the above invention are compounds of Formulae(1) and (2) and isomers thereof, stereoisomeric forms thereof, ormixtures of stereoisomeric forms thereof, and pharmaceuticallyacceptable salt or pro-drug forms thereof with the additional provisosthat: (1) when A is N, R¹ is H, C₁-C₄ alkyl, halo, CN, C₁-C₁₂hydroxyalkyl, C₁-C₄ alkoxyalkyl or SO₂(C₁-C₄ alkyl), R³ is NR^(6a)R^(7a)and R^(6a) is unsubstituted C₁-C₄ alkyl, then R^(7a) is not phenyl,naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, furanyl,benzofuranyl, benzothiazolyl, indolyl or C₃-C₆ cycloalkyl; and (2) A isN, R¹ is H, C₁-C₄ alkyl, halo, CN, C₁-C₁₂ hydroxyalkyl, C₁-C₄alkoxyalkyl or SO₂(C₁-C₄ alkyl), R³ is NR^(6a)R^(7a) and R^(7a) isunsubstituted C₁-C₄ alkyl, then R^(6a) is not phenyl, naphthyl, thienyl,benzothienyl, pyridyl, quinolyl, pyrazinyl, furanyl, benzofuranyl,benzothiazolyl, indolyl or C₃-C₆ cycloalkyl.

[6] Preferred compounds of the above invention also include compounds ofFormulae (1) and (2) and isomers thereof, stereoisomeric forms thereof,or mixtures of stereoisomeric forms thereof, and pharmaceuticallyacceptable salt or pro-drug forms thereof wherein Ar is phenyl, pyridylor 2,3-dihydrobenzofuranyl, each optionally substituted with 1 to 4 R⁴substituents.

[7] Preferred compounds of the above invention also include compounds ofFormulae (1) and (2) and isomers thereof, stereoisomeric forms thereof,or mixtures of stereoisomeric forms thereof, and pharmaceuticallyacceptable salt or pro-drug forms thereof wherein A is N, Z is CR², Aris 2,4-dichlorophenyl, 2,4-dimethylphenyl or 2,4,6-trimethylphenyl, R¹and R² are CH₃, and R³ is NR^(6a)R^(7a).

[11] More preferred compounds of the above invention are compounds andisomers thereof, stereoisomeric forms thereof, or mixtures ofstereoisomeric forms thereof, and pharmaceutically acceptable salt orpro-drug forms thereof wherein A is N.

[12] More preferred compounds of the above invention also includecompounds and isomers thereof, stereoisomeric forms thereof, or mixturesof stereoisomeric forms thereof, and pharmaceutically acceptable salt orpro-drug forms thereof.

[13] More preferred compounds of the above invention also includecompounds and isomers thereof, stereoisomeric forms thereof, or mixturesof stereoisomeric forms thereof, and pharmaceutically acceptable salt orpro-drug forms thereof wherein Ar is phenyl, pyridyl or2,3-dihydrobenzofuranyl and each Ar is optionally substituted with 1 to4 R⁴ substituents.

[14] More preferred compounds of the above invention also includecompounds and isomers thereof, stereoisomeric forms thereof, or mixturesof stereoisomeric forms thereof, and pharmaceutically acceptable salt orpro-drug forms thereof wherein R³ is NR^(6a)R^(7a) or OR⁷.

[15] More preferred compounds of the above invention also includecompounds and isomers thereof, stereoisomeric forms thereof, or mixturesof stereoisomeric forms thereof, and pharmaceutically acceptable salt orpro-drug forms thereof wherein Ar is phenyl, pyridyl or2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to4 R⁴ substituents, and R³ is NR^(6a)R^(7a) or OR⁷.

[16] More preferred compounds of the above invention also includecompounds and isomers thereof, stereoisomeric forms thereof, or mixturesof stereoisomeric forms thereof, and pharmaceutically acceptable salt orpro-drug forms thereof wherein Z is CR².

[17] More preferred compounds of the above invention also includecompounds and isomers thereof, stereoisomeric forms thereof, or mixturesof stereoisomeric forms thereof, and pharmaceutically acceptable salt orpro-drug forms thereof wherein Ar is phenyl, pyridyl or2,3-dihydrobenzofuranyl and each Ar is optionally substituted with 1 to4 R⁴ substituents.

[18] More preferred compounds of the above invention also includecompounds and isomers thereof, stereoisomeric forms thereof, or mixturesof stereoisomeric forms thereof, and pharmaceutically acceptable salt orpro-drug forms thereof wherein R³ is NR^(6a)R^(7a) or OR⁷.

[19] More preferred compounds of the above invention also includecompounds and isomers thereof, stereoisomeric forms thereof, or mixturesof stereoisomeric forms thereof, and pharmaceutically acceptable salt orpro-drug forms thereof wherein R^(6a) is independently selected from:

H,

C₁-C₁₀ alkyl, C₃-C₁₀ alkenyl, C₃-C₁₀ alkynyl, C₁-C₁₀ haloalkyl with 1-10halogens, C₂-C₈ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl,C₅-C₁₀ cycloalkenyl, or C₆-C₁₄ cycloalkenylalkyl, each optionallysubstituted with 1 to 3 substituents independently selected at eachoccurrence from C₁-C₆ alkyl, C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl,cyano, OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵,N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroarylor heterocyclyl,

aryl, aryl(C₁-C₄ alkyl)-, heteroaryl, heteroaryl(C₁-C₄ alkyl)-,heterocyclyl or heterocyclyl(C₁-C₄ alkyl)-; and

R^(7a) is independently selected at each occurrence from:

H,

C₅-C₁₀ alkyl, C₃-C₁₀ alkenyl, C₃-C₁₀ alkynyl, C₁-C₁₀ haloalkyl with 1-10halogens, C₂-C₈ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl,C₅-C₁₀ cycloalkenyl, or C₆-C₁₄ cycloalkenylalkyl, each optionallysubstituted with 1 to 3 substituents independently selected at eachoccurrence from C₁-C₆ alkyl, C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl,cyano, OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵,N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroarylor heterocyclyl,

aryl, aryl(C₁-C₄ alkyl), heteroaryl, heteroaryl(C₁-C₄ alkyl),heterocyclyl or heterocyclyl(C₁-C₄ alkyl);

alternatively, NR⁶R⁷ and NR^(6a)R^(7a) are independently piperidine,pyrrolidine, piperazine, N-methylpiperazine, morpholine orthiomorpholine, each optionally substituted with 1-3 C₁-C₄ alkyl groups.

[20] More preferred compounds of the above invention also includecompounds and isomers thereof, stereoisomeric forms thereof, or mixturesof stereoisomeric forms thereof, and pharmaceutically acceptable salt orpro-drug forms thereof wherein R^(6a) and R^(7a) are identical and areselected from:

C₁-C₄ alkyl or C₃-C₆ cycloalkyl, each optionally substituted with 1 to 3substituents independently selected at each occurrence from C₁-C₆ alkyl,C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹³,—COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³,NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroaryl or heterocyclyl, and

aryl or heteroaryl.

[21] More preferred compounds of the above invention also includecompounds and isomers thereof, stereoisomeric forms thereof, or mixturesof stereoisomeric forms thereof, and pharmaceutically acceptable salt orpro-drug forms thereof wherein R^(6a) is selected from:

H,

C₁-C₁₀ alkyl, C₃-C₁₀ alkenyl, C₃-C₁₀ alkynyl, C₁-C₁₀ haloalkyl with 1-10halogens, C₂-C₈ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl,C₅-C₁₀ cycloalkenyl, or C₆-C₁₄ cycloalkenylalkyl, each optionallysubstituted with 1 to 3 substituents independently selected at eachoccurrence from C₁-C₆ alkyl, C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl,cyano, OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵,N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroarylor heterocyclyl,

aryl, aryl(C₁-C₄ alkyl), heteroaryl, heteroaryl(C₁-C₄ alkyl),heterocyclyl or heterocyclyl(C₁-C₄ alkyl);

R^(7a) is selected from:

C₁-C₄ alkyl and each such C₁-C₄ alkyl is substituted with 1-3substituents independently selected at each occurrence from C₁-C₆ alkyl,C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹³,COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³,NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroaryl or heterocyclyl.

[22] More preferred compounds of the above invention also includecompounds and isomers thereof, stereoisomeric forms thereof, or mixturesof stereoisomeric forms thereof, and pharmaceutically acceptable salt orpro-drug forms thereof wherein one of R^(6a) and R^(7a) is selectedfrom:

C₃-C₆ cycloalkyl, each such C₃-C₆ cycloalkyl optionally substituted with1-3 substituents independently selected at each occurrence from C₁-C₆alkyl, C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl, cyano, OR¹⁵, SH,S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵,NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroaryl or heterocyclyl,

aryl,

heteroaryl or

heterocyclyl,

and the other of R^(6a) and R^(7a) is unsubstituted C₁-C₄ alkyl.

[23] More preferred compounds of the above invention also includecompounds and isomers thereof, stereoisomeric forms thereof, or mixturesof stereoisomeric forms thereof, and pharmaceutically acceptable salt orpro-drug forms thereof wherein R^(6a) and R^(7a) are independently H orC₁-C₁₀ alkyl, each such C₁-C₁₀ alkyl optionally substituted with 1 to 3substituents independently selected at each occurrence from C₁-C₆ alkyl,C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹³,COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵, N(COR¹⁵)₂, R⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³,NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroaryl or heterocyclyl.

[24] More preferred compounds of the above invention also includecompounds and isomers thereof, stereoisomeric forms thereof, or mixturesof stereoisomeric forms thereof, and pharmaceutically acceptable salt orpro-drug forms thereof wherein Ar is phenyl, pyridyl or2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to4 R⁴ substituents, and R³ is NR^(6a)R^(7a) or OR⁷.

[25] More preferred compounds of the above invention also includecompounds and isomers thereof, stereoisomeric forms thereof, or mixturesof stereoisomeric forms thereof, and pharmaceutically acceptable salt orpro-drug forms thereof wherein R^(6a) is independently selected from:

H,

C₁-C₁₀ alkyl, C₃-C₁₀ alkenyl, C₃-C₁₀ alkynyl, C₁-C₁₀ haloalkyl with 1-10halogens, C₂-C₈ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl,C₅-C₁₀ cycloalkenyl, or C₆-C₁₄ cycloalkenylalkyl, each optionallysubstituted with 1 to 3 substituents independently selected at eachoccurrence from C₁-C₆ alkyl, C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl,cyano, OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵,N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroarylor heterocyclyl,

aryl, aryl(C₁-C₄ alkyl)-, heteroaryl, heteroaryl(C₁-C₄ alkyl),heterocyclyl or heterocyclyl(C₁-C₄ alkyl);

R^(7a) is independently selected at each occurrence from:

H,

C₅-C₁₀ alkyl, C₃-C₁₀ alkenyl, C₃-C₁₀ alkynyl, C₁-C₁₀ haloalkyl with 1-10halogens, C₂-C₈ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl,C₅-C₁₀ cycloalkenyl, or C₆-C₁₄ cycloalkenylalkyl, each optionallysubstituted with 1 to 3 substituents independently selected at eachoccurrence from C₁-C₆ alkyl, C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl,cyano, OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵,N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroarylor heterocyclyl,

aryl, aryl(C₁-C₄ alkyl), heteroaryl, heteroaryl(C₁-C₄ alkyl),heterocyclyl or heterocyclyl(C₁-C₄ alkyl),

alternatively, NR⁶R⁷ and NR^(6a)R^(7a) are independently piperidine,pyrrolidine, piperazine, N-methylpiperazine, morpholine orthiomorpholine, each optionally substituted with 1-3 C₁-C₄ alkyl groups.

[26] More preferred compounds of the above invention also includecompounds and isomers thereof, stereoisomeric forms thereof, or mixturesof stereoisomeric forms thereof, and pharmaceutically acceptable salt orpro-drug forms thereof wherein R^(6a) and R^(7a) are identical and areselected from:

C₁-C₄ alkyl or C₃-C₆ cycloalkyl, each optionally substituted with 1 to 3substituents independently selected at each occurrence from C₁-C₆ alkyl,C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹³,—COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³,NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroaryl or heterocyclyl, and

aryl or heteroaryl.

[27] More preferred compounds of the above invention also includecompounds and isomers thereof, stereoisomeric forms thereof, or mixturesof stereoisomeric forms thereof, and pharmaceutically acceptable salt orpro-drug forms thereof wherein R^(6a) and R^(7a) are identical and are

C₁-C₄ alkyl, each such C₁-C₄ alkyl optionally substituted with 1 to 3substituents independently selected at each occurrence from C₁-C₆ alkyl,C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹³,—COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³,NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroaryl or heterocyclyl.

[28] More preferred compounds of the above invention also includecompounds and isomers thereof, stereoisomeric forms thereof, or mixturesof stereoisomeric forms thereof, and pharmaceutically acceptable salt orpro-drug forms thereof wherein R^(6a) is selected from:

H,

C₁-C₁₀ alkyl, C₃-C₁₀ alkenyl, C₃-C₁₀ alkynyl, C₁-C₁₀ haloalkyl with 1-10halogens, C₂-C₈ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl,C₅-C₁₀ cycloalkenyl, or C₆-C₁₄ cycloalkenylalkyl, each optionallysubstituted with 1 to 3 substituents independently selected at eachoccurrence from C₁-C₆ alkyl, C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl,cyano, OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵,N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroarylor heterocyclyl,

aryl, aryl(C₁-C₄ alkyl), heteroaryl, heteroaryl(C₁-C₄ alkyl),heterocyclyl or heterocyclyl(C₁-C₄ alkyl);

R^(7a) is:

C₁-C₄ alkyl and each such C₁-C₄ alkyl is substituted with 1—3substituents independently selected at each occurrence from C₁-C₆ alkyl,C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹³,COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³,NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroaryl or heterocyclyl.

[29] More preferred compounds of the above invention also includecompounds and isomers thereof, stereoisomeric forms thereof, or mixturesof stereoisomeric forms thereof, and pharmaceutically acceptable salt orpro-drug forms thereof wherein one of R^(6a) and R^(7a) is selectedfrom:

C₃-C₆ cycloalkyl, each such C₃-C₆ cycloalkyl optionally substituted with1-3 substituents independently selected at each occurrence from C₁-C₆alkyl, C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl, cyano, OR¹⁵, SH,S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵,NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroaryl or heterocyclyl,

aryl,

heteroaryl or

heterocyclyl,

and the other of R^(6a) and R^(7a) is unsubstituted C₁-C₄ alkyl.

[30] More preferred compounds of the above invention also includecompounds and isomers thereof, stereoisomeric forms thereof, or mixturesof stereoisomeric forms thereof, and pharmaceutically acceptable salt orpro-drug forms thereof wherein R^(6a) and R^(7a) are independently H orC₁-C₁₀ alkyl, each such C₁-C₁₀ alkyl optionally substituted with 1 to 3substituents independently selected at each occurrence from C₁-C₆ alkyl,C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹³,COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵, N(COR¹⁵)₂, R⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³,NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroaryl or heterocyclyl.

[31] More preferred compounds of the above invention also includecompounds and isomers thereof, stereoisomeric forms thereof, or mixturesof stereoisomeric forms thereof, and pharmaceutically acceptable salt orpro-drug forms thereof wherein

Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar isoptionally substituted with 1 to 4 R⁴ substituents,

R³ is NR^(6a)R^(7a) or OR⁷ and

R¹ and R² are independently selected from H, C₁-C₄ alkyl, C₃-C₆cycloalkyl, C₄-C₁₀ cycloalkylalkyl.

[32] More preferred compounds of the above invention also includecompounds and isomers thereof, stereoisomeric forms thereof, or mixturesof stereoisomeric forms thereof, and pharmaceutically acceptable salt orpro-drug forms thereof wherein R^(6a) is independently selected from:

H,

C₁-C₁₀ alkyl, C₃-C₁₀ alkenyl, C₃-C₁₀ alkynyl, C₁-C₁₀ haloalkyl with 1-10halogens, C₂-C₈ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl,C₅-C₁₀ cycloalkenyl, or C₆-C₁₄ cycloalkenylalkyl, each optionallysubstituted with 1 to 3 substituents independently selected at eachoccurrence from C₁-C₆ alkyl, C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl,cyano, OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵,N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroarylor heterocyclyl,

aryl, aryl(C₁-C₄ alkyl)-, heteroaryl, heteroaryl(C₁-C₄ alkyl),heterocyclyl or heterocyclyl(C₁-C₄ alkyl);

R^(7a) is independently selected at each occurrence from:

H,

C₅-C₁₀ alkyl, C₃-C₁₀ alkenyl, C₃-C₁₀ alkynyl, C₁-C₁₀ haloalkyl with 1-10halogens, C₂-C₈ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl,C₅-C₁₀ cycloalkenyl, or C₆-C₁₄ cycloalkenylalkyl, each optionallysubstituted with 1 to 3 substituents independently selected at eachoccurrence from C₁-C₆ alkyl, C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl,cyano, OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵,N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroarylor heterocyclyl,

aryl, aryl(C₁-C₄ alkyl), heteroaryl, heteroaryl(C₁-C₄ alkyl),heterocyclyl or heterocyclyl(C₁-C₄ alkyl),

alternatively, NR⁶R⁷ and NR^(6a)R^(7a) are independently piperidine,pyrrolidine, piperazine, N-methylpiperazine, morpholine orthiomorpholine, each optionally substituted with 1-3 C₁-C₄ alkyl groups.

[33] More preferred compounds of the above invention also includecompounds and isomers thereof, stereoisomeric forms thereof, or mixturesof stereoisomeric forms thereof, and pharmaceutically acceptable salt orpro-drug forms thereof wherein R^(6a) and R^(7a) are identical and areselected from:

C₁-C₄ alkyl or C₃-C₆ cycloalkyl, each optionally substituted with 1 to 3substituents independently selected at each occurrence from C₁-C₆ alkyl,C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹³,—COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵, N(COR¹⁵)2, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³,NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroaryl or heterocyclyl, and

aryl or heteroaryl.

[34] More preferred compounds of the above invention also includecompounds and isomers thereof, stereoisomeric forms thereof, or mixturesof stereoisomeric forms thereof, and pharmaceutically acceptable salt orpro-drug forms thereof wherein R^(6a) and R^(7a) are identical and are

C₁-C₄ alkyl, each such C₁-C₄ alkyl optionally substituted with 1 to 3substituents independently selected at each occurrence from C₁-C₆ alkyl,C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹³,—COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵, N(COR¹⁵)2, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³,NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroaryl or heterocyclyl.

[35] More preferred compounds of the above invention also includecompounds and isomers thereof, stereoisomeric forms thereof, or mixturesof stereoisomeric forms thereof, and pharmaceutically acceptable salt orpro-drug forms thereof wherein R^(6a) is selected from:

H,

C₁—C₁₀ alkyl, C₃-C₁₀ alkenyl, C₃-C₁₀ alkynyl, C₁-C₁₀ haloalkyl with 1-10halogens, C₂-C₈ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl,C₅-C₁₀ cycloalkenyl, or C₆-C₁₄ cycloalkenylalkyl, each optionallysubstituted with 1 to 3 substituents independently selected at eachoccurrence from C₁-C₆ alkyl, C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl,cyano, OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵,N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroarylor heterocyclyl,

aryl, aryl(C₁-C₄ alkyl), heteroaryl, heteroaryl(C₁-C₄ alkyl),heterocyclyl or heterocyclyl(C₁-C₄ alkyl);

R^(7a) is:

C₁-C₄ alkyl and each such C₁-C₄ alkyl is substituted with 1-3substituents independently selected at each occurrence from C₁-C₆ alkyl,C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)nR¹³,COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³,NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroaryl or heterocyclyl.

[36] More preferred compounds of the above invention also includecompounds and isomers thereof, stereoisomeric forms thereof, or mixturesof stereoisomeric forms thereof, and pharmaceutically acceptable salt orpro-drug forms thereof wherein one of R^(6a) and R^(7a) is selectedfrom:

C₃-C₆ cycloalkyl, each such C₃-C₆ cycloalkyl optionally substituted with1-3 substituents independently selected at each occurrence from C₁-C₆alkyl, C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl, cyano, OR¹⁵, SH,S(O)nR¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵,NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroaryl or heterocyclyl,

aryl,

heteroaryl or

heterocyclyl,

and the other of R^(6a) and R^(7a) is unsubstituted C₁-C₄ alkyl.

[37] More preferred compounds of the above invention also includecompounds and isomers thereof, stereoisomeric forms thereof, or mixturesof stereoisomeric forms thereof, and pharmaceutically acceptable salt orpro-drug forms thereof wherein R^(6a) and R^(7a) are independently H orC₁-C₁₀ alkyl, each such C₁-C₁₀ alkyl optionally substituted with 1 to 3substituents independently selected at each occurrence from C₁-C₆ alkyl,C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹³,COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵, N(COR¹⁵⁾ ₂, R⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³,NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroaryl or heterocyclyl.

[38] Specifically preferred compounds of the above invention arecompounds of Formula (50)

and isomers thereof, stereoisomeric forms thereof, or mixtures ofstereoisomeric forms thereof, and pharmaceutically acceptable salt orpro-drug forms thereof, selected from the group consisting of:

a compound of Formula (50) wherein R³ is —NHCH(n-Pr)₂, R^(4a) is Cl,R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —N(Et)(n-Bu), R^(4a) is Cl,R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —(n-Pr) (CH₂cPr), R^(4a) is Cl,R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —N(CH₂CH₂OMe)₂, R^(4a) is Cl,R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —NHCH(Et) (n-Bu), R^(4a) is Cl,R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —NHCH(Et) (CH₂OMe), R^(4a) isCl, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —NHCH(CH₂OMe)₂, R^(4a) is Cl,R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —N(Et)₂, R^(4a) is Cl, R^(4b)is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —NHCH(CH₂OEt)₂, R^(4a) is Cl,R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —NHCH(Et)₂, R^(4a) is Cl,R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —N(Me) (Ph), R^(4a) is Cl,R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —N(n-Pr)₂, R^(4a) is Cl, R^(4b)is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —NHCH(Et) (n-Pr), R^(4a) is Cl,R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —NHCH(CH₂OMe)₂, R^(4a) is Me,R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is Me;

a compound of Formula (50) wherein R³ is —NHCH(CH₂OMe)₂, R^(4a) is Me,R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —N(CH₂CH₂OMe)₂, R^(4a) is Me,R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —NHCH(Et) (CH₂OMe), R^(4a) isMe, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —NHCH(Et)₂, R^(4a) is Me,R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —OEt, R^(4a) is Cl, R^(4b) isH, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —N(Et)₂, R^(4a) is Me, R^(4b)is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —N(CH₂CN)₂, R^(4a) is Me,R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —NHCH(Me) (CH₂OMe), R^(4a) isMe, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —OCH(Et) (CH₂OMe), R^(4a) isMe, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —N(n-Pr) (CH₂cPr), R^(4a) isMe, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —NHCH(Me) (CH₂N(Me)2), R^(4a)is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

compound of Formula (50) wherein R³ is —N(cPr) (CH₂CH₂CN), R^(4a) is Me,R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —N(n-Pr) (CH₂CH₂CN), R^(4a) isMe, R^(4b) is H, R^(4c) is Me, R⁴d is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —N(n-Bu) (CH₂CN), R^(4a) is Me,R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —NHCH(Et) (CH₂OMe), R^(4a) isMe, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is Me;

a compound of Formula (50) wherein R³ is —NHCH(Et)₂, R^(4a) is Me,R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is Me;

a compound of Formula (50) wherein R³ is —N(CH₂CH₂OMe)₂, R^(4a) is Me,R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is Me;

a compound of Formula (50) wherein R³ is —NHCH(CH₂OMe)₂, R^(4a) is Br,R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —NHCH(Et) (CH₂OMe), R^(4a) isBr, R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —N(Et)₂, R^(4a) is Me, R^(4b)is H, R^(4c) is Me, R^(4d) is H and R^(4e) is Me;

a compound of Formula (50) wherein R³ is —NHCH(CH₂OEt)₂, R^(4a) is Me,R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is Me;

a compound of Formula (50) wherein R³ is —NHCH(CH₂CH₂OMe) (CH₂OMe)₂,R^(4a) is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is Me;

a compound of Formula (50) wherein R³ is morpholino, R^(4a) is Me,R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —N(CH₂CH₂OMe)₂, R^(4a) is Br,R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —NHCH(Et)₂, R^(4a) is Br,R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —N(Et)₂, R^(4a) is Br, R^(4b)is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —NH(c-Pr), R^(4a) is Me, R^(4b)is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —NHCH(CH₂OMe)₂, R^(4a) is CN,R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —N(c-Pr) (CH₂CH₂CN), R^(4a) isMe, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is Me;

a compound of Formula (50) wherein R³ is —NCH (CH₂OMe)₂, R^(4a) is Me,R^(4b) is H, R^(4c) is Br, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —NHCH(CH₂OMe) (CH₂CH₂OMe),R^(4a) is Me, R^(4b) is H, R^(4c) is Br, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —NHCH(CH₂OMe)₂, R^(4a) is Me,R^(4b) is H, R^(4c) is OMe, R^(4d) is Me and R^(4e) is H;

a compound of Formula (50) wherein R³ is —N(CH₂CH₂OMe)₂, R^(4a) is Me,R^(4b) is H, R^(4c) is OMe, R^(4d) is Me and R^(4e) is H;

a compound of Formula (50) wherein R³ is —NHCH(Et)₂, R^(4a) is Me,R^(4b) is H, R^(4c) is OMe, R^(4d) is Me and R^(4e) is H;

a compound of Formula (50) wherein a compound of Formula (50) wherein R³is —N(Et)₂, R^(4a) is Me, R^(4b) is H, R^(4c) is OMe, R^(4d) is Me andR^(4e) is H;

a compound of Formula (50) wherein R³ is —NHCH(CH₂OMe)₂, R^(4a) is Cl,R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —NHCH(Et) (CH₂OMe), R^(4a) isCl, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —N(CH₂CH₂OMe)₂, R^(4a) is Cl,R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —NHCH(CH₂OMe) (CH₂CH₂OMe),R^(4a) is Cl, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —N(c-Pr) (CH₂CH₂CN), R^(4a) isMe, R^(4b) is H, R^(4c) is OMe, R^(4d) is Me and R^(4e) is H;

a compound of Formula (50) wherein R³ is —N(c-Pr) (CH₂CH₂CN), R^(4a) isCl, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is (S)—NHCH(CH₂OMe) (CH₂CH₂OMe),R^(4a) is Cl, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —NHCH(CH₂OMe) (CH₂CH₂OMe),R^(4a) is Cl, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —NHCH(Et)₂, R^(4a) is Me,R^(4b) is H, R^(4c) is Br, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —N(CH₂CH₂OMe)₂, R^(4a) is Me,R^(4b) is H, R^(4c) is Br, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —NH(CH₂OMe) (CH₂-iPr), R^(4a)is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —N(CH₂CH₂OMe)₂, R^(4a) is Me,R^(4b) is H, R^(4c) is H, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —N(CH₂CH₂OMe)₂, R^(4a) is Me,R^(4b) is H, R^(4c) is NMe₂, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —NHCH(CH₂OMe) (n-Pr), R^(4a) isMe, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —NHCH(CH₂OEt) (Et), R^(4a) isMe, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R is H;

a compound of Formula (50) wherein R³ is —NHCH(CH₂OMe) (CH₂CH₂OMe),R^(4a) is Me, R^(4b) is H, R^(4c) is NMe₂, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —N(Et)₂, R^(4a) is Me, R^(4b)is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —NHCH(Et)₂, R^(4a) is Me,R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —N(CH₂CH₂OMe)₂, R^(4a) is Me,R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —NHCH(CH₂OMe)₂, R^(4a) is Me,R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —N(Et)₂, R^(4a) is Me, R^(4b)is H, R^(4c) is Br, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —N(Et)₂, R^(4a) is Cl, R^(4b)is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —NHCH(Et)₂, R^(4a) is Cl,R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —NHCH(Et)₂, R^(4a) is Me,R^(4b) is H, R^(4c) is NMe₂, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is (S)—NHCH(CH₂OMe) (CH₂CH₂OMe),R^(4a) is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —NHCH(CH₂OMe) (CH₂CH₂OMe),R^(4a) is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is (S)—NHCH(CH₂OMe) (CH₂CH₂OMe),R^(4a) is Me, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —NHCH(CH₂OMe) (CH₂CH₂OMe),R^(4a) is Me, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —N(c-Pr) (CH₂CH₂CN), R^(4a) isMe, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —NH(Et) (CH₂CN), R^(4a) is Me,R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —N(Et)₂, R^(4a) is Me, R^(4b)is Me, R^(4c) is OMe, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —N(CH₂CH₂OMe) (CH₂CH₂OH),R^(4a) is Cl, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —N(CH₂CH₂OMe)₂, R^(4a) is Me,R^(4b) is Me, R^(4c) is OMe, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —NHCH(Et)₂, R^(4a) is Me,R^(4b) is Me, R^(4c) is OMe, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —N(CH₂c-Pr) (n-Pr), R^(4a) isMe, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —N(c-Pr) (CH₂CH₂CN), R^(4a) isMe, R^(4b) is Me, R^(4c) is OMe, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —NHCH (Et)₂, R^(4a) is Cl,R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —N(Et)₂, R^(4a) is Cl, R^(4b)is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —N(CH₂CH₂OMe)₂, R^(4a) is Cl,R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —NHCH(Et) (CH₂OMe), R^(4a) isCl, R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —N(Et)₂, R^(4a) is Cl, R^(4b)is H, R^(4c) is CN, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —N(c-Pr) (CH₂CH₂CN), R^(4a) isCl, R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H;

a compound of Formula (50) wherein R³ is —NHCH(CH₂OH)₂, R^(4a) is Cl,R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H; and

a compound of Formula (50) wherein R³ is N(CH₂CH₂OMe)₂, R^(4a) is Me,R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H.

[39] More specifically preferred is4-(bis-(2-methoxyethyl)amino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-[1,5-a]-pyrazolo-1,3,5-triazineand isomers thereof, stereoisomeric forms thereof, or mixtures ofstereoisomeric forms thereof, and pharmaceutically acceptable salt orpro-drug forms thereof.

[40] More specifically preferred is4-(bis-(2-methoxyethyl)amino)-2,7-dimethyl-8-(2,5-dimethyl-4-methoxyphenyl)-[1,5-a]-pyrazolo-1,3,5-triazineand isomers thereof, stereoisomeric forms thereof, or mixtures ofstereoisomeric forms thereof, and pharmaceutically acceptable salt orpro-drug forms thereof.

[41] More preferred are compounds of the above invention are compoundsand isomers thereof, stereoisomeric forms thereof, or mixtures ofstereoisomeric forms thereof, and pharmaceutically acceptable salt orpro-drug forms thereof wherein A is CR.

[42] More preferred compounds of the above invention also includecompounds and isomers thereof, stereoisomeric forms thereof, or mixturesof stereoisomeric forms thereof, and pharmaceutically acceptable salt orpro-drug forms thereof.

[43] More preferred compounds of the above invention also includecompounds and isomers thereof, stereoisomeric forms thereof, or mixturesof stereoisomeric forms thereof, and pharmaceutically acceptable salt orpro-drug forms thereof wherein Ar is phenyl, pyridyl or2,3-dihydrobenzofuranyl and each Ar is optionally substituted with 1 to4 R⁴ substituents.

[44] More preferred compounds of the above invention also includecompounds and isomers thereof, stereoisomeric forms thereof, or mixturesof stereoisomeric forms thereof, and pharmaceutically acceptable salt orpro-drug forms thereof wherein R³ is NR^(6a)R^(7a) or OR⁷.

[45] More preferred compounds of the above invention also includecompounds and isomers thereof, stereoisomeric forms thereof, or mixturesof stereoisomeric forms thereof, and pharmaceutically acceptable salt orpro-drug forms thereof wherein Ar is phenyl, pyridyl or2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to4 R⁴ substituents, and R³ is NR^(6a)R^(7a) or OR⁷.

[46] More preferred compounds of the above invention also includecompounds and isomers thereof, stereoisomeric forms thereof, or mixturesof stereoisomeric forms thereof, and pharmaceutically acceptable salt orpro-drug forms thereof wherein Z is CR².

[47] More preferred compounds of the above invention also includecompounds and isomers thereof, stereoisomeric forms thereof, or mixturesof stereoisomeric forms thereof, and pharmaceutically acceptable salt orpro-drug forms thereof wherein Ar is phenyl, pyridyl or2,3-dihydrobenzofuranyl and each Ar is optionally substituted with 1 to4 R⁴ substituents.

[48] More preferred compounds of the above invention also includecompounds and isomers thereof, stereoisomeric forms thereof, or mixturesof stereoisomeric forms thereof, and pharmaceutically acceptable salt orpro-drug forms thereof wherein R³ is NR^(6a)R^(7a) or OR⁷.

[49] More preferred compounds of the above invention also includecompounds and isomers thereof, stereoisomeric forms thereof, or mixturesof stereoisomeric forms thereof, and pharmaceutically acceptable salt orpro-drug forms thereof wherein Ar is phenyl, pyridyl or2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to4 R⁴ substituents, and R³ is Nr^(6a)R^(7a) or OR⁷.

[50] More preferred compounds of the above invention also includecompounds and isomers thereof, stereoisomeric forms thereof, or mixturesof stereoisomeric forms thereof, and pharmaceutically acceptable salt orpro-drug forms thereof wherein R^(6a) and R^(7a) are independently H orC₁-C₁₀ alkyl, and each such C₁-C₁₀ alkyl is optionally substituted with1 to 3 substituents independently selected at each occurrence from C₁-C₆alkyl, C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl, cyano, OR¹⁵, SH,S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵, N(COR¹⁵)₂, R⁸CONR¹⁶R¹⁵,NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroaryl or heterocyclyl.

[51] More preferred compounds of the above invention also includecompounds and isomers thereof, stereoisomeric forms thereof, or mixturesof stereoisomeric forms thereof, and pharmaceutically acceptable salt orpro-drug forms thereof wherein

Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar isoptionally substituted with 1 to 4 R⁴ substituents,

R³ is Nr^(6a)R^(7a) or OR⁷ and

R¹ and R² are independently selected from H, C₁-C₄ alkyl, C₃-C₆cycloalkyl, C₄-C₁₀ cycloalkylalkyl.

[52] More preferred compounds of the above invention also includecompounds and isomers thereof, stereoisomeric forms thereof, or mixturesof stereoisomeric forms thereof, and pharmaceutically acceptable salt orpro-drug forms thereof wherein R^(6a) and R^(7a) are independently H orC₁-C₁₀ alkyl, and each such C₁-C₁₀ alkyl is optionally substituted with1 to 3 substituents independently selected at each occurrence from C₁-C₆alkyl, C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl, cyano, OR¹⁵, SH,S(O)_(n)R₁₃, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵, N(COR¹⁵)₂, R⁸CONR¹⁶R¹⁵,NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroaryl or heterocyclyl.

[53] Specifically preferred compounds of the above invention arecompounds of Formula (51)

and isomers thereof, stereoisomeric forms thereof, or mixtures ofstereoisomeric forms thereof, and pharmaceutically acceptable salt orpro-drug forms thereof selected from the group consisting of:

a compound of Formula (51) wherein R³ is —NHCH(n-Pr)₂, R^(4a) is Me,R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is —NHCH(CH₂OMe)₂, R^(4a) is Me,R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is —N(CH₂CH₂OMe)₂, R^(4a) is Me,R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is —N(c-Pr) (CH₂CH₂CN), R^(4a) isMe, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is —N(CH₂CH₂OMe)₂, R^(4a) is Cl,R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is —NHCH(CH₂OMe)₂, R^(4a) is Cl,R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is —NHCH(Et)₂, R^(4a) is Cl,R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is —N(Et)₂, R^(4a) is Me, R^(4b)is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is —N(n-Pr) (CH₂CH₂CN), R^(4a) isMe, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is —N(n-Bu) (CH₂CH₂CN), R^(4a) isMe, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is —NHCH(n-Pr) (CH₂OMe), R^(4a) isMe, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is —NHCH(Et)₂, R^(4a) is Me,R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is —NHCH(CH₂OMe)₂, R^(4a) is Me,R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is (S)—NH(CH₂CH₂OMe)CH₂OMe, R^(4a)is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is —NH(CH₂CH₂OMe)CH₂OMe, R^(4a) isMe, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is —N(CH₂CH₂OMe)₂, R^(4a) is Me,R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is —NH(Et), R^(4a) is Me, R^(4b)is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is —NHCH(n-Pr)₂, R^(4a) is Me,R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is —NHCH(CH₂OMe)₂, R^(4a) is Me,R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is (S)—NH(CH₂CH₂OMe)CH₂OMe, R^(4a)is Me, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is —NH(CH₂CH₂OMe)CH₂OMe, R^(4a) isMe, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is —N(n-Pr) (CH₂CH₂CN), R^(4a) isMe, R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is —N(Et)₂, R^(4a) is Me, R^(4b)is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is (S)—NH(CH₂CH₂OMe)CH₂OMe, R^(4a)is Cl, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is —NH(CH₂CH₂OMe)CH₂OMe, R^(4a) isCl, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is —N(Et)₂, R^(4a) is Cl, R^(4b)is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is —N(c-Pr) (CH₂CH₂CN), R^(4a) isMe, R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is —N(c-Pr) (CH₂CH₂CN), R^(4a) isCl, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is —NHCH(n-Pr) (CH₂OMe), R^(4a) isMe, R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is —NHCH(n-Pr) (CH₂OMe), R^(4a) isCl, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is —NHCH(Et)₂, R^(4a) is Br,R^(4b) is H, R^(4c) is OMe, R^(4d) is OMe and R^(4e) is H;

a compound of Formula (51) wherein R³ is —NHCH(Et)₂, R^(4a) is Br,R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is —N(CH₂CH₂OMe)₂, R^(4a) is Br,R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is —NHCH(CH₂OMe)₂, R^(4a) is Br,R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is —N(Et)₂, R^(4a) is Me, R^(4b)is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is —N(Et)₂, R^(4a) is Cl, R^(4b)is H, R^(4c) is OMe, R^(4d) is OMe and R^(4e) is H;

a compound of Formula (51) wherein R³ is —NHCH(Et)₂, R^(4a) is Cl,R^(4b) is H, R^(4c) is OMe, R^(4d) is OMe and R^(4e) is H;

a compound of Formula (51) wherein R³ is —N(CH₂CH₂OMe)₂, R^(4a) is Cl,R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is —NHCH(CH₂OMe)₂, R^(4a) is Cl,R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is —N(Pr) (CH₂CH₂CN), R^(4a) isCl, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is —N(Bu) (Et), R^(4a) is Cl,R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is —NHCH(Et)CH₂OMe, R^(4a) is Cl,R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

compound of Formula (51) wherein R³ is —NHCH(Et)₂, R^(4a) is Cl, R^(4b)is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is —NHCH(Et)₂, R^(4a) is Me,R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is —NHCH(Et)₂, R^(4a) is Cl,R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is —NHCH(Et)₂, R^(4a) is Me,R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H;

a compound of Formula (51) wherein R³ is —NEt₂, R^(4a) is Me, R^(4b) isH, R^(4c) is OMe, R^(4d) is H and R^(4e) is H; and

a compound of Formula (51) wherein R³ is —N(Pr) (CH₂CH₂CN), R^(4a) isMe, R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H.

[54] More specifically preferred is7-(3-pentylamino)-2,5-dimethyl-3-(2-methyl-4-methoxyphenyl)-[1,5-a]-pyrazolopyrimidineand isomers thereof, stereoisomeric forms thereof, or mixtures ofstereoisomeric forms thereof, and pharmaceutically acceptable salt orpro-drug forms thereof.

[55] More specifically preferred is7-(Diethylamino)-2,5-dimethyl-3-(2-methyl-4-methoxyphenyl-[1,5-a]-pyrazolopyrimidineand isomers thereof, stereoisomeric forms thereof, or mixtures ofstereoisomeric forms thereof, and pharmaceutically acceptable salt orpro- drug forms thereof.

[56] More specifically preferred is7-(N-(3-cyanopropyl)—N-propylamino)-2,5-dimethyl-3-(2,4-dimethylphenyl)-[1,5-a]-pyrazolopyrimidineand isomers thereof, stereoisomeric forms thereof, or mixtures ofstereoisomeric forms thereof, and pharmaceutically acceptable salt orpro-drug forms thereof.

The present invention also provides pharmaceutical compositionscomprising compounds of Formulae (1) and (2) and a pharmaceuticallyacceptable carrier.

[1] The present invention still further comprises a method of treatingaffective disorder, anxiety, depression, headache, irritable bowelsyndrome, post-traumatic stress disorder, supranuclear palsy, immunesuppression, Alzheimer's disease, gastrointestinal diseases, anorexianervosa or other feeding disorder, drug addiction, drug or alcoholwithdrawal symptoms, inflammatory diseases, cardiovascular orheart-related diseases, fertility problems, human immunodeficiency virusinfections, hemorrhagic stress, obesity, infertility, head and spinalcord traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis,hypoglycemia or a disorder the treatment of which can be effected orfacilitated by antagonizing CRF, including but not limited to disordersinduced or facilitated by CRF, in mammals comprising administering tothe mammal a therapeutically effective amount of a compound of Formulae(1) or (2):

and isomers thereof, stereoisomeric forms thereof, or mixtures ofstereoisomeric forms thereof, and pharmaceutically acceptable salt formsthereof, wherein:

Z is N or CR²;

Ar is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl,furanyl, thienyl, benzothienyl, benzofuranyl, 2,3-dihydrobenzofuranyl,2,3-dihydrobenzothienyl, indanyl, 1,2-benzopyranyl,3,4-dihydro-1,2-benzopyranyl, tetralinyl, each Ar optionally substitutedwith 1 to 5 R⁴ groups and each Ar is attached to an unsaturated carbonatom;

R¹ is independently selected at each occurrence from H, C₁-C₄ alkyl,C₂-C₄ alkenyl, C₂-C₄ alkynyl, halo, CN, C₁-C₄ haloalkyl, C₁-C₁₂hydroxyalkyl, C₂-C₁₂ alkoxyalkyl, C₂-C₁₀ cyanoalkyl, C₃-C₆ cycloalkyl,C₄-C₁₀ cycloalkylalkyl, NR⁹R¹⁰, C₁-C₄ alkyl-NR⁹R¹⁰, NR⁹COR¹⁰, OR¹¹, SHor S(O)_(n)R¹²;

R² is selected from H, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆cycloalkyl, C₄-C₁₀ cycloalkylalkyl, C₁-C₄ hydroxyalkyl, halo, CN,—NR⁶R⁷, NR⁹COR¹⁰, —NR⁶S(O)_(n)R⁷, S(O)_(n)NR⁶R⁷, C₁-C₄ haloalkyl, —OR⁷,SH or —S(O)_(n)R¹²;

R³ is selected from:

H, OR⁷, SH, S(O)_(n)R¹³, COR⁷ ₁, CO₂R⁷, OC(O)R¹³, NR⁸COR⁷, N(COR⁷)₂,NR⁸CONR⁶R⁷, NR⁸CO₂R¹³, NR⁶R⁷, NR^(6a)R^(7a), N(OR⁷)R⁶, CONR⁶R⁷, aryl,heteroaryl and heterocyclyl, or

C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈cycloalkenyl, C₄-C₁₂ cycloalkylalkyl or C₆-C₁₀ cycloalkenylalkyl, eachoptionally substituted with 1 to 3 substituents independently selectedat each occurrence from C₁-C₆ alkyl, C₃-C₆ cycloalkyl, halo, C₁-C₄haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³,NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl,heteroaryl and heterocyclyl;

R⁴ is independently selected at each occurrence from: C₁-C₁₀ alkyl,C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₆ cycloalkyl, C₄-C₁₂cycloalkylalkyl, NO₂, halo, CN, C₁-C₄ haloalkyl, NR⁶R⁷, NR⁸COR⁷,NR⁸CO₂R⁷, COR⁷, OR⁷, CONR⁶R⁷, CO(NOR⁹)R⁷, CO₂R⁷, or S(O)_(n)R⁷, whereeach such C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₆ cycloalkyland C₄-C₁₂ cycloalkylalkyl are optionally substituted with 1 to 3substituents independently selected at each occurrence from C₁-C₄ alkyl,NO₂, halo, CN, NR⁶R⁷, NR⁸COR⁷, NR⁸CO₂R⁷, COR⁷ OR⁷, CONR⁶R⁷, CO₂R⁷,CO(NOR⁹)R⁷, or S(O)_(n)R⁷;

R⁶, R⁷, R^(6a) and R^(7a) are independently selected at each occurrencefrom:

H,

C₁-C₁₀ alkyl, C₃-C₁₀ alkenyl, C₃-C₁₀ alkynyl, C₁-C₁₀ haloalkyl with 1-10halogens, C₂-C₈ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl,C₅-C₁₀ cycloalkenyl, or C₆-C₁₄ cycloalkenylalkyl, each optionallysubstituted with 1 to 3 substituents independently selected at eachoccurrence from C₁-C₆ alkyl, C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl,cyano, OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵,N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroarylor heterocyclyl,

aryl, aryl(C₁-C₄ alkyl), heteroaryl, heteroaryl(C₁-C₄ alkyl),heterocyclyl or heterocyclyl(C₁-C₄ alkyl);

alternatively, NR⁶R⁷ and NR^(6a)R^(7a) are independently piperidine,pyrrolidine, piperazine, N-methylpiperazine, morpholine orthiomorpholine, each optionally substituted with 1—3 C₁-C₄ alkyl groups;

R⁸ is independently selected at each occurrence from H or C₁-C₄ alkyl;

R⁹ and R¹⁰ are independently selected at each occurrence from H, C₁-C₄alkyl, or C₃-C₆ cycloalkyl;

R¹¹ is selected from H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₃-C₆cycloalkyl;

R¹² is C₁-C₄ alkyl or C₁-C₄ haloalkyl;

R¹³ is selected from C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₂-C₈ alkoxyalkyl,C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl, aryl, aryl(C₁-C₄ alkyl)-,heteroaryl or heteroaryl(C₁-C₄ alkyl)-;

R¹⁴ is selected from C₁-C₁₀ alkyl, C₃-C₁₀ alkenyl, C₃-C₁₀ alkynyl, C₃-C₈cycloalkyl, or C₄-C₁₂ cycloalkylalkyl, each optionally substituted with1 to 3 substituents independently selected at each occurrence from C₁-C₆alkyl, C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl, cyano, OR¹⁵, SH,S(O)_(n)R¹⁵, COR¹⁵, CO₂R¹⁵, OC(O)R¹⁵, NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵,NR⁸CO₂R¹⁵, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, and C₁-C₆ alkylthio, C₁-C₆ alkylsulfinyland C₁-C₆ alkylsulfonyl;

R¹⁵ and R¹⁶ are independently selected at each occurrence from H, C₁-C₆alkyl, C₃-C₁₀ cycloalkyl, C₄-C₁₆ cycloalkylalkyl, except that forS(O)_(n)R¹⁵, R¹⁵ cannot be H;

aryl is phenyl or naphthyl, each optionally substituted with 1 to 5substituents independently selected at each occurrence from C₁-C₆ alkyl,C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹⁵,COR¹⁵, CO₂R¹⁵, OC(O)R¹⁵, NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹⁵,NR¹⁶R¹⁵ and CONR¹⁶R¹⁵;

heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, pyranyl,quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl,pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl,isoxazolyl, pyrazolyl, 2,3-dihydrobenzothienyl or2,3-dihydrobenzofuranyl, each being optionally substituted with 1 to 5substituents independently selected at each occurrence from C₁-C₆ alkyl,C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹⁵,—COR¹⁵, CO₂R¹⁵, OC(O)R¹⁵, NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹⁵,NR¹⁶R¹⁵, and CONR¹⁶R¹⁵;

heterocyclyl is saturated or partially saturated heteroaryl, optionallysubstituted with 1 to 5 substituents independently selected at eachoccurrence from C₁-C₆ alkyl, C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl,cyano, OR¹⁵, SH, S(O)_(n)R¹⁵, COR¹⁵, CO₂R¹⁵, OC(O)R¹⁵, NR⁸COR¹⁵,N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹⁵, NR¹⁵R¹⁶, and CONR¹⁶R¹⁵;

n is independently at each occurrence 0, 1 or 2;

with the proviso that when Z is CR², then R³ is not NR⁶R⁷, NR^(6a)R^(7a)or OR⁷.

[2] Further preferred methods of the present invention are methodswherein in the compound of Formulae (1) or (2), Ar is phenyl, pyridyl or2,3-dihydrobenzofuranyl, each optionally substituted with 1 to 4 R⁴substituents.

[3] Further preferred methods of the present invention are methodswherein in the compound of Formulae (1) or (2), A is N, Z is CR², Ar is2,4-dichlorophenyl, 2,4-dimethylphenyl or 2,4,6-trimethylphenyl, R¹ andR² are CH₃, and R³ is Nr^(6a)R^(7a).

[4] The present invention further comprises compounds of Formulae (1) or(2):

and isomers thereof, stereoisomeric forms thereof, or mixtures ofstereoisomeric forms thereof, and pharmaceutically acceptable salt formsthereof wherein:

Z is N or CR²;

Ar is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl,furanyl, thienyl, benzothienyl, benzofuranyl, 2,3-dihydrobenzofuranyl,2,3-dihydrobenzothienyl, indanyl, 1,2-benzopyranyl,3,4-dihydro-1,2-benzopyranyl, tetralinyl, each Ar optionally substitutedwith 1 to 5 R⁴ groups and each Ar is attached to an unsaturated carbonatom;

R¹ is independently selected at each occurrence from H, C₁-C₄ alkyl,C₂-C₄ alkenyl, C₂-C₄ alkynyl, halo, CN, C₁-C₄ haloalkyl, C₁ C₁₂hydroxyalkyl, C₂-C₁₂ alkoxyalkyl, C₂-C₁₀ cyanoalkyl, C₃-C₆ cycloalkyl,C₄-C₁₀ cycloalkylalkyl, NR⁹R¹⁰, C₁-C₄ alkyl-NR⁹R¹⁰, NR⁹COR¹⁰, OR¹¹, SHor S(O)_(n)R¹²;

R² is selected from H, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆cycloalkyl, C₄-C₁₀ cycloalkylalkyl, C₁-C₄ hydroxyalkyl, halo, CN,—NR⁶R⁷, NR⁹COR¹⁰, —NR⁶S(O)_(n)R⁷, S(O)_(n)NR⁶R⁷, C₁-C₄ haloalkyl, —OR⁷,SH or —S(O)_(n)R¹²;

R³ is selected from:

H, OR⁷, SH, S(O)_(n)R^(13,) COR⁷, CO₂R⁷, OC(O)R¹³, NR⁸COR⁷, N(COR⁷)₂,NR⁸CONR⁶R⁷, NR⁸CO₂R¹³, NR⁶R⁷, NR^(6a)R^(7a), N(OR⁷)R⁶, CONR⁶R⁷, aryl,heteroaryl and heterocyclyl, or

C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈cycloalkenyl, C₄-C₁₂ cycloalkylalkyl or C₆-C₁₀ cycloalkenylalkyl, eachoptionally substituted with 1 to 3 substituents independently selectedat each occurrence from C₁-C₆ alkyl, C₃-C₆ cycloalkyl, halo, C₁-C₄haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³,NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R^(13,) NR¹⁶R¹⁵, CONR¹⁶R¹⁵,aryl, heteroaryl and heterocyclyl;

R⁴ is independently selected at each occurrence from: C₁-C₁₀ alkyl,C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₆ cycloalkyl, C₄-C₁₂cycloalkylalkyl, NO₂, halo, CN, C₁-C₄ haloalkyl, NR⁶R⁷, NR⁸COR⁷,NR⁸CO₂R⁷, COR⁷, OR⁷, CONR⁶R⁷, CO(NOR⁹)R⁷, CO₂R⁷, or S(O)_(n)R⁷, whereeach such C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₆ cycloalkyland C₄-C₁₂ cycloalkylalkyl are optionally substituted with 1 to 3substituents independently selected at each occurrence from C₁-C₄ alkyl,NO₂, halo, CN, NR⁶R⁷, NR⁸COR⁷, NR⁸CO₂R⁷, COR⁷, OR⁷, CONR⁶R⁷, CO₂R⁷,CO(NOR⁹)R⁷, or S(O)_(n)R⁷;

R⁶, R7, R^(6a) and R^(7a) are independently selected at each occurrencefrom:

H,

C₁-C₁₀ alkyl, C₃-C₁₀ alkenyl, C₃-C₁₀ alkynyl, C₁-C₁₀ haloalkyl with 1-10halogens, C₂-C₈ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl,C₅-C₁₀ cycloalkenyl, or C₆-C₁₄ cycloalkenylalkyl, each optionallysubstituted with 1 to 3 substituents independently selected at eachoccurrence from C₁-C₆ alkyl, C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl,cyano, OR¹⁵, SH, S(O)_(n)R^(13,) COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵,N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R^(13,) NR¹⁶R^(15,) CONR¹⁶R¹⁵, aryl,heteroaryl or heterocyclyl,

aryl, aryl(C₁-C₄ alkyl), heteroaryl, heteroaryl(C₁-C₄ alkyl),heterocyclyl or heterocyclyl(C₁-C₄ alkyl),

alternatively, NR⁶R⁷ and NR^(6a)R^(7a) are independently piperidine,pyrrolidine, piperazine, N-methylpiperazine, morpholine orthiomorpholine, each optionally substituted with 1-3 C₁-C₄ alkyl groups;

R⁸ is independently selected at each occurrence from H or C₁-C₄ alkyl;

R⁹ and R¹⁰ are independently selected at each occurrence from H, C₁-C₄alkyl, or C₃-C₆ cycloalkyl;

R¹¹ is selected from H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₃-C₆cycloalkyl;

R¹² is C₁-C₄ alkyl or C₁-C₄ haloalkyl;

R¹³ is selected from C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₂-C₈ alkoxyalkyl,C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl, aryl, aryl(C₁-C₄ alkyl)-,heteroaryl or heteroaryl(C₁-C₄ alkyl)-;

R¹⁴ is selected from C₁-C₁₀ alkyl, C₃-C₁₀ alkenyl, C₃-C₁₀ alkynyl, C₃-C₈cycloalkyl, or C₄-C₁₂ cycloalkylalkyl, each optionally substituted with1 to 3 substituents independently selected at each occurrence from C₁-C₆alkyl, C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl, cyano, OR¹⁵, SH,S(O)_(n)R¹⁵ COR¹⁵, CO₂R¹⁵, OC(O)R¹⁵, NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵,NR⁸CO₂R¹⁵, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, and C₁-C₆ alkylthio, C₁-C₆ alkylsulfinyland C₁-C₆ alkylsulfonyl;

R¹⁵ and R¹⁶ are independently selected at each occurrence from H, C₁-C₆alkyl, C₃-C₁₀ cycloalkyl, C₄-C₁₆ cycloalkylalkyl, except that forS(O)_(n)R¹⁵, R¹⁵ cannot be H;

aryl is phenyl or naphthyl, each optionally substituted with 1 to 5substituents independently selected at each occurrence from C₁-C₆ alkyl,C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹⁵,COR¹⁵, CO₂R¹⁵, OC(O)R¹⁵, NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹⁵,NR¹⁶R¹⁵, and CONR¹⁶R¹⁵;

heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, pyranyl,quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl,pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl,isoxazolyl, pyrazolyl, 2,3-dihydrobenzothienyl or2,3-dihydrobenzofuranyl, each being optionally substituted with 1 to 5substituents independently selected at each occurrence from C₁-C₆ alkyl,C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹⁵,—COR¹⁵, CO₂R¹⁵, OC(O)R¹⁵, NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹⁵,NR¹⁶R¹⁵, and CONR¹⁶R¹⁵;

heterocyclyl is saturated or partially saturated heteroaryl, optionallysubstituted with 1 to 5 substituents independently selected at eachoccurrence from C₁-C₆ alkyl, C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl,cyano, OR¹⁵, SH, S(O)_(n)R¹⁵, COR¹⁵, CO₂R¹⁵, OC(O)R¹⁵, NR⁸COR¹⁵,N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹⁵, NR¹⁵R¹⁶, and CONR¹⁶R¹⁵;

n is independently at each occurrence 0, 1 or 2;

 with the provisos that:

(1) when Z is CR² and R² is H and R³ is OCOR¹³ and R⁷ is H, then R¹ isnot H, OH or SH;

(2) when Z is CR² and R¹ is CH₃ or C₂H₅ and R² is H, and R³ is H, CH₃,C₂H₅, C₆H₅, n-C₃H₇, i-C₃H₇, SH or SCH₃, then Ar is not phenyl orm-CH₃-phenyl;

(3) when Z is CR² and R² is —NR⁶SO₂R⁷ or —SO₂NR⁶R⁷, then R³ is not SH;and

(4) when Z is CR², then R³ is not NR⁶R⁷, NR^(6a)R^(7a) or OR⁷.

[5] Further preferred compounds of the present invention includecompounds of claim 4 and isomers thereof, stereoisomeric forms thereof,or mixtures of stereoisomeric forms thereof, and pharmaceuticallyacceptable salt forms thereof wherein Ar is phenyl, pyridyl or2,3-dihydrobenzofuranyl, each optionally substituted with 1 to 4 R⁴substituents.

[6] The present invention further provides for a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of claim 4.

[7] The present invention further provides for a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of claim 5.

[8] Further preferred compounds of the present invention includecompounds of Formula (2) of claim 4 and isomers thereof, stereoisomericforms thereof, or mixtures of stereoisomeric forms thereof, andpharmaceutically acceptable salt forms thereof.

[9] Further preferred compounds of the present invention includecompounds of claim 8 and isomers thereof, stereoisomeric forms thereof,or mixtures of stereoisomeric forms thereof, and pharmaceuticallyacceptable salt forms thereof wherein Ar is phenyl, pyridyl or2,3-dihydrobenzofuranyl and each Ar is optionally substituted with 1 to4 R⁴ substituents.

[10] Further preferred compounds of the present invention includecompounds of claim 8 and isomers thereof, stereoisomeric forms thereof,or mixtures of stereoisomeric forms thereof, and pharmaceuticallyacceptable salt forms thereof wherein R³ is NR^(6a)R^(7a) or OR⁷.

[11] Further preferred compounds of the present invention includecompounds of claim 8 and isomers thereof, stereoisomeric forms thereof,or mixtures of stereoisomeric forms thereof, and pharmaceuticallyacceptable salt forms thereof wherein Ar is phenyl, pyridyl or2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to4 R⁴ substituents, and R³ is NR^(6a)R^(7a) or OR⁷.

[12] Further preferred compounds of the present invention includecompounds of claim 4 and isomers thereof, stereoisomeric forms thereof,or mixtures of stereoisomeric forms thereof, and pharmaceuticallyacceptable salt forms thereof wherein Z is CR².

[13] Further preferred compounds of the present invention includecompounds of claim 12 and isomers thereof, stereoisomeric forms thereof,or mixtures of stereoisomeric forms thereof, and pharmaceuticallyacceptable salt forms thereof wherein Ar is phenyl, pyridyl or2,3-dihydrobenzofuranyl and each Ar is optionally substituted with 1 to4 R⁴ substituents.

[14] Further preferred compounds of the present invention includecompounds of claim 4 and isomers thereof, stereoisomeric forms thereof,or mixtures of stereoisomeric forms thereof, and pharmaceuticallyacceptable salt forms thereof wherein:

R^(6a) is independently selected from:

H,

C₁-C₁₀ alkyl, C₃-C₁₀ alkenyl, C₃-C₁₀ alkynyl, C₁-C₁₀ haloalkyl with 1-10halogens, C₂-C₈ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl,C₅-C₁₀ cycloalkenyl, or C₆-C₁₄ cycloalkenylalkyl, each optionallysubstituted with 1 to 3 substituents independently selected at eachoccurrence from C₁-C₆ alkyl, C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl,cyano, OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵,N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroarylor heterocyclyl,

aryl, aryl(C₁-C₄ alkyl)-, heteroaryl, heteroaryl(C₁-C₄ alkyl)-,heterocyclyl or heterocyclyl(C₁-C₄ alkyl)-; and

R^(7a) is independently selected at each occurrence from:

H,

C₅-C₁₀ alkyl, C₃-C₁₀ alkenyl, C₃-C₁₀ alkynyl, C₁-C₁₀ haloalkyl with 1-10halogens, C₂-C₈ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl,C₅-C₁₀ cycloalkenyl, or C₆-C₁₄ cycloalkenylalkyl, each optionallysubstituted with 1 to 3 substituents independently selected at eachoccurrence from C₁-C₆ alkyl, C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl,cyano, OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵,N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroarylor heterocyclyl,

aryl, aryl(C₁-C₄ alkyl), heteroaryl, heteroaryl(C₁-C₄ alkyl),heterocyclyl or heterocyclyl(C₁-C₄ alkyl);

alternatively, NR⁶R⁷ and NR^(6a)R^(7a) are independently piperidine,pyrrolidine, piperazine, N-methylpiperazine, morpholine orthiomorpholine, each optionally substituted with 1-3 C₁-C₄ alkyl groups.

[15] Further preferred compounds of the present invention includecompounds of claim 4 and isomers thereof, stereoisomeric forms thereof,or mixtures of stereoisomeric forms thereof, and pharmaceuticallyacceptable salt forms thereof wherein:

R^(6a) and R^(7a) are identical and are selected from:

C₁-C₄ alkyl or C₃-C₆ cycloalkyl, each optionally substituted with 1 to 3substituents independently selected at each occurrence from C₁-C₆ alkyl,C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹³,—COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³,NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroaryl or heterocyclyl, and

aryl or heteroaryl.

[16] Further preferred compounds of the present invention includecompounds of claim 4 and isomers thereof, stereoisomeric forms thereof,or mixtures of stereoisomeric forms thereof, and pharmaceuticallyacceptable salt forms thereof wherein:

R^(6a) is selected from:

H,

C₁-C₁₀ alkyl, C₃-C₁₀ alkenyl, C₃-C₁₀ alkynyl, C₁-C₁₀ haloalkyl with 1-10halogens, C₂-C₈ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄—C₁₂ cycloalkylalkyl,C₅-C₁₀ cycloalkenyl, or C₆-C₁₄ cycloalkenylalkyl, each optionallysubstituted with 1 to 3 substituents independently selected at eachoccurrence from C₁-C₆ alkyl, C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl,cyano, OR¹⁵, SH, S(O)_(n)R^(13,) COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵,N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroarylor heterocyclyl,

aryl, aryl(C₁-C₄ alkyl), heteroaryl, heteroaryl(C₁-C₄ alkyl),heterocyclyl or heterocyclyl(C₁-C₄ alkyl);

R^(7a) is selected from:

C₁-C₄ alkyl and each such C₁-C₄ alkyl is substituted with 1-3substituents independently selected at each occurrence from C₁-C₆ alkyl,C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹³,COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³,NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroaryl or heterocyclyl.

[17] Further preferred compounds of the present invention includecompounds of claim 4 and isomers thereof, stereoisomeric forms thereof,or mixtures of stereoisomeric forms thereof, and pharmaceuticallyacceptable salt forms thereof wherein:

one of R^(6a) and R^(7a) is selected from:

C₃-C₆ cycloalkyl, each such C₃-C₆ cycloalkyl optionally substituted with1-3 substituents independently selected at each occurrence from C₁-C₆alkyl, C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl, cyano, OR¹⁵, SH,S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵,NR⁸CO₂R^(13,) NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroaryl or heterocyclyl,

aryl,

heteroaryl or

heterocyclyl,

and the other of R^(6a) and R^(7a) is unsubstituted C₁-C₄ alkyl.

[18] Further preferred compounds of the present invention includecompounds of claim 4 and isomers thereof, stereoisomeric forms thereof,or mixtures of stereoisomeric forms thereof, and pharmaceuticallyacceptable salt forms thereof wherein R^(6a) and R^(7a) areindependently H or C₁-C₁₀ alkyl, each such C₁-C₁₀ alkyl optionallysubstituted with 1 to 3 substituents independently selected at eachoccurrence from C₁-C₆ alkyl, C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl,cyano, OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵,N(COR¹⁵)₂, R⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroarylor heterocyclyl.

[19] Further preferred compounds of the present invention includecompounds of claim 14 and isomers thereof, stereoisomeric forms thereof,or mixtures of stereoisomeric forms thereof, and pharmaceuticallyacceptable salt forms thereof wherein Ar is phenyl, pyridyl or2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to4 R⁴ substituents.

[20] Further preferred compounds of the present invention includecompounds of claim 15 and isomers thereof, stereoisomeric forms thereof,or mixtures of stereoisomeric forms thereof, and pharmaceuticallyacceptable salt forms thereof wherein Ar is phenyl, pyridyl or2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to4 R⁴ substituents.

[21] Further preferred compounds of the present invention includecompounds of claim 16 and isomers thereof, stereoisomeric forms thereof,or mixtures of stereoisomeric forms thereof, and pharmaceuticallyacceptable salt forms thereof wherein Ar is phenyl, pyridyl or2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to4 R⁴ substituents.

[22] Further preferred compounds of the present invention includecompounds of claim 17 and isomers thereof, stereoisomeric forms thereof,or mixtures of stereoisomeric forms thereof, and pharmaceuticallyacceptable salt forms thereof wherein Ar is phenyl, pyridyl or2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to4 R⁴ substituents.

[23] Further preferred compounds of the present invention includecompounds of claim 18 and isomers thereof, stereoisomeric forms thereof,or mixtures of stereoisomeric forms thereof, and pharmaceuticallyacceptable salt forms thereof wherein Ar is phenyl, pyridyl or2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to4 R⁴ substituents.

[24] Further preferred compounds of the present invention includecompounds of claim 4 and isomers thereof, stereoisomeric forms thereof,or mixtures of stereoisomeric forms thereof, and pharmaceuticallyacceptable salt forms thereof wherein

Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar isoptionally substituted with 1 to 4 R⁴ substituents,

R¹ and R² are independently selected from H, C₁-C₄ alkyl, C₃-C₆cycloalkyl, C₄-C₁₀ cycloalkylalkyl.

[25] Further preferred compounds of the present invention includecompounds of claim 14 and isomers thereof, stereoisomeric forms thereof,or mixtures of stereoisomeric forms thereof, and pharmaceuticallyacceptable salt forms thereof wherein

Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar isoptionally substituted with 1 to 4 R⁴ substituents,

R¹ and R² are independently selected from H, C₁-C₄ alkyl, C₃-C₆cycloalkyl, C₄-C₁₀ cycloalkylalkyl.

[26] Further preferred compounds of the present invention includecompounds of claim 15 and isomers thereof, stereoisomeric forms thereof,or mixtures of stereoisomeric forms thereof, and pharmaceuticallyacceptable salt forms thereof wherein

Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar isoptionally substituted with 1 to 4 R⁴ substituents,

R¹ and R² are independently selected from H, C₁-C₄ alkyl, C₃-C₆cycloalkyl, C₄-C₁₀ cycloalkylalkyl.

[27] Further preferred compounds of the present invention includecompounds of claim 16 and isomers thereof, stereoisomeric forms thereof,or mixtures of stereoisomeric forms thereof, and pharmaceuticallyacceptable salt forms thereof wherein

Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar isoptionally substituted with 1 to 4 R⁴ substituents,

R¹ and R² are independently selected from H, C₁-C₄ alkyl, C₃-C₆cycloalkyl, C₄-C₁₀ cycloalkylalkyl.

[28] Further preferred compounds of the present invention includecompounds of claim 17 and isomers thereof, stereoisomeric forms thereof,or mixtures of stereoisomeric forms thereof, and pharmaceuticallyacceptable salt forms thereof wherein

Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar isoptionally substituted with 1 to 4 R⁴ substituents,

R¹ and R² are independently selected from H, C₁-C₄ alkyl, C₃-C₆cycloalkyl, C₄-C₁₀ cycloalkylalkyl.

[29] Further preferred compounds of the present invention includecompounds of claim 18 and isomers thereof, stereoisomeric forms thereof,or mixtures of stereoisomeric forms thereof, and pharmaceuticallyacceptable salt forms thereof wherein

Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar isoptionally substituted with 1 to 4 R⁴ substituents,

R¹ and R² are independently selected from H, C₁-C₄ alkyl, C₃-C₆cycloalkyl, C₄-C₁₀ cycloalkylalkyl.

[30] Further preferred compounds of the present invention includecompounds of claim 24 and isomers thereof, stereoisomeric forms thereof,or mixtures of stereoisomeric forms thereof, and pharmaceuticallyacceptable salt forms thereof wherein

R^(6a) and R^(7a) are independently H or C₁-C₁₀ alkyl, each such C₁-C₁₀alkyl optionally substituted with 1 to 3 substituents independentlyselected at each occurrence from C₁-C₆ alkyl, C₃-C₆ cycloalkyl, halo,C₁-C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³,NR⁸COR¹⁵, N(COR¹⁵)₂, R⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl,heteroaryl or heterocyclyl.

[31] Further preferred compounds of the present invention includecompounds of claim 4 and isomers thereof, stereoisomeric forms thereof,or mixtures of stereoisomeric forms thereof, and pharmaceuticallyacceptable salt forms thereof wherein R¹ is independently selected ateach occurrence from H, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, halo,CN, C₁-C₄ haloalkyl, C₁-C₁₂ hydroxyalkyl, C₂-C₁₂ alkoxyalkyl, C₃-C₆cycloalkyl, C₄-C₁₀ cycloalkylalkyl.

[32] Further preferred compounds of the present invention includecompounds of claim 4 and isomers thereof, stereoisomeric forms thereof,or mixtures of stereoisomeric forms thereof, and pharmaceuticallyacceptable salt forms thereof wherein R² is selected from H, C₁-C₄alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆ cycloalkyl, C₄-C₁₀cycloalkylalkyl, C₁-C₄ hydroxyalkyl, halo, CN, —NR⁶R⁷, C₁-C₄ haloalkyl,—OR⁷.

[33] Further preferred compounds of the present invention includecompounds of claim 4 and isomers thereof, stereoisomeric forms thereof,or mixtures of stereoisomeric forms thereof, and pharmaceuticallyacceptable salt forms thereof wherein R⁴ is independently selected ateach occurrence from: C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₃-C₆ cycloalkyl,C₄-C₁₂ cycloalkylalkyl, halo, CN, C₁-C₄ haloalkyl, NR⁶R⁷, COR⁷, OR⁷,where each such C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₃-C₆ cycloalkyl andC₄-C₁₂ cycloalkylalkyl are optionally substituted with 1 to 3substituents independently selected at each occurrence from C₁-C₄ alkyl,NR⁶R⁷, COR⁷ OR⁷, CO₂R⁷.

[34] Further preferred compounds of the present invention includecompounds of claim 4 and isomers thereof, stereoisomeric forms thereof,or mixtures of stereoisomeric forms thereof, and pharmaceuticallyacceptable salt forms thereof wherein R⁴ is independently selected ateach occurrence from: H, C₁-C₁₀ alkyl, C₁-C₄ alkoxy, halo, CN and—NR⁶R⁷.

[35] The present invention further provides for a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of claim 5, 14, 15 and19.

[36] The present invention further provides for a method of treatingaffective disorder, anxiety, depression, headache, irritable bowelsyndrome, post-traumatic stress disorder, supranuclear palsy, immunesuppression, Alzheimer's disease, gastrointestinal diseases, anorexianervosa or other feeding disorder, drug addiction, drug or alcoholwithdrawal symptoms, inflammatory diseases, cardiovascular orheart-related diseases, fertility problems, human immunodeficiency virusinfections, hemorrhagic stress, obesity, infertility, head and spinalcord traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis,hypoglycemia or a disorder the treatment of which can be effected orfacilitated by antagonizing CRF, including but not limited to disordersinduced or facilitated by CRF, in mammals comprising administering tothe mammal a therapeutically effective amount of a compound of claimclaim 4, 5, 14, 15 and 19.

Many compounds of this invention have one or more asymmetric centers orplanes. Unless otherwise indicated, all chiral (enantiomeric anddiastereomeric) and racemic forms are included in the present invention.Many geometric isomers of olefins, C═N double bonds, and the like canalso be present in the compounds, and all such stable isomers arecontemplated in the present invention. The compounds may be isolated inoptically active or racemic forms. It is well known in the art how toprepare optically active forms, such as by resolution of racemic formsor by synthesis from optically active starting materials. All chiral,(enantiomeric and diastereomeric) and racemic forms and all geometricisomeric forms of a structure are intended, unless the specificstereochemistry or isomer form is specifically indicated.

The term “alkyl” includes both branched and straight-chain alkyl havingthe specified number of carbon atoms. Commonly used abbreviations havethe following meanings: Me is methyl, Et is ethyl, Pr is propyl, Bu isbutyl. As is conventional, in a chemical structure drawing, a straightsingle bond attached to an atom at one end but with no atom designationat the other end indicates the presence of a methyl group at theunattached end of the bond. The prefix “n” means a straight chain alkyl.The prefix “c” means a cycloalkyl. The prefix “(S)” means the Senantiomer and the prefix “(R)” means the R enantiomer. Alkenyl”includes hydrocarbon chains of either a straight or branchedconfiguration and one or more unsaturated carbon-carbon bonds which mayoccur in any stable point along the chain, such as ethenyl, propenyl,and the like. “Alkynyl” includes hydrocarbon chains of either a straightor branched configuration and one or more triple carbon-carbon bondswhich may occur in any stable point along the chain, such as ethynyl,propynyl and the like. “Haloalkyl” is intended to include both branchedand straight-chain alkyl having the specified number of carbon atoms,substituted with 1 or more halogen; “alkoxy” represents an alkyl groupof indicated number of carbon atoms attached through an oxygen bridge;“cycloalkyl” is intended to include saturated ring groups, includingmono-, bi- or poly-cyclic ring systems, such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, and so forth. “Halo” or “halogen” includesfluoro, chloro, bromo, and iodo.

The term “substituted”, as used herein, means that one or more hydrogenon the designated atom is replaced with a selection from the indicatedgroup, provided that the designated atom's normal valency is notexceeded, and that the substitution results in a stable compound. When asubstitent is keto (i.e., ═O), then 2 hydrogens on the atom arereplaced.

Combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds. By “stable compound” or“stable structure” is meant a compound that is sufficiently robust tosurvive isolation to a useful degree of purity from a reaction mixture,and formulation into an efficacious therapeutic agent.

The term “appropriate amino acid protecting group” means any group knownin the art of organic synthesis for the protection of amine orcarboxylic acid groups. Such amine protecting groups include thoselisted in Greene and Wuts, “Protective Groups in Organic Synthesis” JohnWiley & Sons, New York (1991) and “The Peptides: Analysis, Synthesis,Biology, Vol. 3, Academic Press, New York (1981), the disclosure ofwhich is hereby incorporated by reference. Any amine protecting groupknown in the art can be used. Examples of amine protecting groupsinclude, but are not limited to, the following: 1) acyl types such asformyl, trifluoroacetyl, phthalyl, and p-toluenesulfonyl; 2) aromaticcarbamate types such as benzyloxycarbonyl (Cbz) and substitutedbenzyloxycarbonyls, 1-(p-biphenyl)-1-methylethoxycarbonyl, and9-fluorenylmethyloxycarbonyl (Fmoc); 3) aliphatic carbamate types suchas tert-butyloxycarbonyl (Boc), ethoxycarbonyl,diisopropylmethoxycarbonyl, and allyloxycarbonyl; 4) cyclic alkylcarbamate types such as cyclopentyloxycarbonyl and adamantyloxycarbonyl;5) alkyl types such as triphenylmethyl and benzyl; 6) trialkylsilanesuch as trimethylsilane; and 7) thiol containing types such asphenylthiocarbonyl and dithiasuccinoyl.

The term “pharmaceutically acceptable salts” includes acid or base saltsof the compounds of Formulae (1) and (2). Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like.

Pharmaceutically acceptable salts of the compounds of the invention canbe prepared by reacting the free acid or base forms of these compoundswith a stoichiometric amount of the appropriate base or acid in water orin an organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,1985, p. 1418, the disclosure of which is hereby incorporated byreference. “Prodrugs” are considered to be any covalently bondedcarriers which release the active parent drug of formula (I) or (II) invivo when such prodrug is administered to a mammalian subject. Prodrugsof the compounds of formula (I) and (II) are prepared by modifyingfunctional groups present in the compounds in such a way that themodifications are cleaved, either in routine manipulation or in vivo, tothe parent compounds. Prodrugs include compounds wherein hydroxy, amine,or sulfhydryl groups are bonded to any group that, when administered toa mammalian subject, cleaves to form a free hydroxyl, amino, orsulfhydryl group, respectively. Examples of prodrugs include, but arenot limited to, acetate, formate and benzoate derivatives of alcohol andamine functional groups in the compounds of formulas (I) and (II); andthe like.

The term “therapeutically effective amount” of a compound of thisinvention means an amount effective to antagonize abnormal level of CRFor treat the symptoms of affective disorder, anxiety or depression in ahost.

Syntheses

Some compounds of Formula (1) may be prepared from intermediatecompounds of Formula (7), using the procedures outlined in Scheme 1:

Compounds of Formula (7) (where Y is O) may be treated with ahalogenating agent or sulfonylating agent in the presence or absence ofa base in the presence or absence of an inert solvent at reactiontemperatures ranging from −80° C. to 250° C. to give products of Formula(8) (where X is halogen, alkanesulfonyloxy, arylsulfonyloxy orhaloalkane-sulfonyloxy). Halogenating agents include, but are notlimited to, SOCl₂, POCl₃, PCl₃, PCl₅, POBr₃, PBr₃ or PBr₅. Sulfonylatingagents include, but are not limited to, alkanesulfonyl halides oranhydrides (such as methanesulfonyl chloride or methanesulfonic acidanhydride), arylsulfonyl halides or anhydrides (such asp-toluenesulfonyl chloride or anhydride) or haloalkylsulfonyl halides oranhydrides (preferably trifluoromethanesulfonic anhydride). Bases mayinclude, but are not limited to, alkali metal hydrides (preferablysodium hydride), alkali metal alkoxides (1 to 6 carbons)(preferablysodium methoxide or sodium ethoxide), alkaline earth metal hydrides,alkali metal dialkylamides (preferably lithium di-isopropylamide),alkali metal bis(trialkylsilyl)amides (preferably sodiumbis(trimethylsilyl)amide), trialkyl amines (preferablyN,N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines(preferably pyridine). Inert solvents may include, but are not limitedto, lower alkanenitriles (1 to 6 carbons, preferably acetonitrile),dialkyl ethers (preferably diethyl ether), cyclic ethers (preferablytetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferablydimethylformamide), N,N-dialkylacetamides (preferablydimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one),dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons(preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1to 10 halogens (preferably dichloromethane). Preferred reactiontemperatures range from −20° C. to 100° C.

Compounds of Formula (8) may be reacted with compounds of Formula R³H(where R³ is defined as above except R³ is not SH, COR⁷, CO₂R⁷, aryl orheteroaryl) in the presence or absence of a base in the presence orabsence of an inert solvent at reaction temperatures ranging from −80 to250° C. to generate compounds of Formula (1). Bases may include, but arenot limited to, alkali metal hydrides (preferably sodium hydride),alkali metal alkoxides (1 to 6 carbons)(preferably sodium methoxide orsodium ethoxide), alkaline earth metal hydrides, alkali metaldialkylamides (preferably lithium di-isopropylamide), alkali metalcarbonates, alkali metal bicarbonates, alkali metalbis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide),trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine) or aromaticamines (preferably pyridine). Inert solvents may include, but are notlimited to, alkyl alcohols (1 to 8 carbons, preferably methanol orethanol), lower alkanenitriles (1 to 6 carbons, preferablyacetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers(preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides(preferably dimethylformamide), N,N-dialkylacetamides (preferablydimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one),dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons(preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1to 10 halogens (preferably dichloromethane). Preferred reactiontemperatures range from 0° C. to 140° C.

Scheme 2 delineates the procedures for converting intermediate compoundsof Formula (7) (where Y is S) to some compounds of Formula (1).

Compounds of Formula (7) (where Y is S) may be treated with analkylating agent R¹³X (where R¹³ is defined as above, except R¹³ is notaryl or heteroaryl) in the presence or absence of a base in the presenceor absence of an inert solvent at reaction temperatures ranging from−80° C. to 250° C. Bases may include, but are not limited to, alkalimetal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to6 carbons)(preferably sodium methoxide or sodium ethoxide), alkalineearth metal hydrides, alkali metal dialkylamides (preferably lithiumdi-isopropylamide), alkali metal carbonates, alkali metal hydroxides,alkali metal bis(trialkylsilyl)amides (preferably sodiumbis(trimethylsilyl)amide), trialkyl amines (prefereablyN,N-di-isopropyl-N-ethyl amine or triethyl amine) or aromatic amines(preferably pyridine). Inert solvents may include, but are not limitedto, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol),lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkylethers (preferably diethyl ether), cyclic ethers (preferablytetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferablydimethylformamide), N,N-dialkylacetamides (preferablydimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one),dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons(preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1to 10 halogens (preferably dichloromethane). Preferred reactiontemperatures range from −80° C. to 100° C.

Compounds of Formula (12) (Formula (1) where R³ is SR¹³) may then bereacted with compounds of Formula R³H to give compounds of Formula (1),using the same conditions and reagents as were used for the conversionof compounds of Formula (8) to compounds of Formula (1) as outlined forScheme 1 above. Alternatively, compounds of Formula (12) (Formula (1)where R³ is SR¹³) may be oxidized to compounds of Formula (13) (Formula(1) where R³ is S(O)_(n)R^(l3), n is 1,2) by treatment with an oxidizingagent in the presence of an inert solvent at temperatures ranging from−80° C. to 250° C. . Oxidizing agents include, but are not limited to,hydrogen peroxide, alkane or aryl peracids (preferably peracetic acid orm-chloro-perbenzoic acid), dioxirane, oxone, or sodium periodate. Inertsolvents may include, but are not limited to, alkanones (3 to 10carbons, preferably acetone), water, alkyl alcohols (1 to 6 carbons),aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane) orcombinations thereof. The choices of oxidant and solvent are known tothose skilled in the art (cf. Uemura, S., Oxidation of Sulfur, Seleniumand Tellurium, in Comprehensive Organic Synthesis, Trost, B. M. ed.,(Elmsford, N.Y.: Pergamon Press, 1991), 7, 762-769). Preferred reactiontemperatures range from −20° C. to 100° C. . Compounds of Formula (13)(Formula (1) where R³ is S(O)_(n)R¹³, n is 1,2) may then be reacted withcompounds of Formula R³H to give compounds of Formula (1), using thesame conditions and reagents as were used for the conversion ofcompounds of Formula (8) to compounds of Formula (1) as outlined forScheme (1) above.

Compounds of Formula (1), where R³ may be —NR⁸COR⁷, —N(COR⁷)₂,—NR⁸CONR⁶R⁷, —NR⁸CO₂R¹³, —NR⁶R⁷, —NR⁸SO₂R⁷may be prepared from compoundsof Formula (7), where Y is NH, by the procedures depicted in Scheme 3.

Reaction of compounds of Formula (7), where Y is NH, with alkylatingagents, sulfonylating agents or acylating agents or sequential reactionswith combinations thereof, in the presence or absence of a base in aninert solvent at reaction temperatures ranging from −80° C. to 250° C.may afford compounds of Formula (1), where R³ may be —NR⁸COR⁷,—N(COR⁷)₂,—NR⁸CONR⁶R⁷, —NR⁸CO₂R¹³, —NR⁶R⁷, —NR⁸SO₂R⁷. Alkylating agentsmay include, but are not limited to, C₁-C₁₀ alkyl -halides, -tosylates,-mesylates or -triflates; C₁-C₁₀ haloalkyl(1-10 halogens)-halides,-tosylates, -mesylates or -triflates; C₂-C₈ alkoxyalkyl-halides,-tosylates, -mesylates or -triflates; C₃-C₆ cycloalkyl-halides,-tosylates, -mesylates or -triflates; C₄-C₁₂ cycloalkylalkyl-halides,-tosylates, -mesylates or -triflates; aryl(C₁-C₄ alkyl)-halides,-tosylates, -mesylates or -triflates; heteroaryl(C₁ -C₄ alkyl)-halides,-tosylates, -mesylates or -triflates; or heterocyclyl(C₁-C₄alkyl)-halides, -tosylates, -mesylates or -triflates. Acylating agentsmay include, but are not limited to, C₁-C₁₀ alkanoyl halides oranhydrides, C₁-C₁₀ haloalkanoyl halides or anhydrides with 1-10halogens, C₂-C₈ alkoxyalkanoyl halides or anhydrides, C₃-C₆cycloalkanoyl halides or anhydrides, C₄-C₁₂ cycloalkylalkanoyl halidesor anhydrides, aroyl halides or anhydrides, aryl(C₁-C₄) alkanoyl halidesor anhydrides, heteroaroyl halides or anhydrides, heteroaryl(C₁-C₄)alkanoyl halides or anhydrides, heterocyclylcarboxylic acid halides oranhydrides or heterocyclyl(C₁-C₄) alkanoyl halides or anhydrides.Sulfonylating agents include, but are not limited to, C₁-C₁₀alkylsulfonyl halides or anhydrides, C₁-C₁₀ haloalkylsulfonyl halides oranhydrides with 1-10 halogens, C₂-C₈ alkoxyalkylsulfonyl halides oranhydrides, C₃-C₆ cycloalkylsulfonyl halides or anhydrides, C₄-C₁₂cycloalkylalkylsulfonyl halides or anhydrides, arylsulfonyl halides oranhydrides, aryl(C₁-C₄ alkyl)-, heteroarylsulfonyl halides oranhydrides, heteroaryl(C₁-C₄ alkyl)sulfonyl halides or anhydrides,heterocyclylsulfonyl halides or anhydrides or heterocyclyl(C₁-C₄alkyl)sulfonyl halides or anhydrides. Bases may include, but are notlimited to, alkali metal hydrides (preferably sodium hydride), alkalimetal alkoxides (1 to 6 carbons)(preferably sodium methoxide or sodiumethoxide), alkaline earth metal hydrides, alkali metal dialkylamides(preferably lithium di-isopropylamide), alkali metal carbonates, alkalimetal bis(trialkylsilyl)amides (preferably sodiumbis(trimethylsilyl)amide), trialkyl amines (prefereablydi-isopropylethyl amine) or aromatic amines (preferably pyridine). Inertsolvents may include, but are not limited to, alkyl alcohols (1 to 8carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6carbons, preferably acetonitrile), dialkyl ethers (preferably diethylether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane),N,N-dialkylformamides (preferably dimethylformamide),N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides(preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferablydimethylsulfoxide) or aromatic hydrocarbons (preferably benzene ortoluene). Preferred reaction temperatures range from 0° C. to 100° C.

Scheme 4 delineates procedures, which may be employed to prepareintermediate compounds of Formula (7), where Y is O, S and Z is CR².

Compounds of the formula ArCH₂CN are reacted with compounds of theformula R²COR^(b), where R² is defined above and R^(b) is halogen,cyano, lower alkoxy (1 to 6 carbons) or lower alkanoyloxy (1 to 6carbons), in the presence of a base in an inert solvent at reactiontemperatures ranging from −78° C. to 200° C. to afford compounds ofFormula (3). Bases may include, but are not limited to, alkali metalhydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6carbons)(preferably sodium methoxide or sodium ethoxide), alkaline earthmetal hydrides, alkali metal dialkylamides (preferably lithiumdi-isopropylamide), alkali metal carbonates, alkali metal hydroxides,alkali metal bis(trialkylsilyl)amides (preferably sodiumbis(trimethylsilyl)amide), trialkyl amines (preferablyN,N-di-isopropyl-N-ethyl amine) or aromatic amines (preferablypyridine). Inert solvents may include, but are not limited to, alkylalcohols (1 to 8 carbons, preferably methanol or ethanol), loweralkanenitriles (1 to 6 carbons, preferably acetonitrile), water, dialkylethers (preferably diethyl ether), cyclic ethers (preferablytetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferablydimethylformamide), N,N-dialkylacetamides (preferablydimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one),dialkylsulfoxides (preferably dimethylsulfoxide) or aromatichydrocarbons (preferably benzene or toluene). Preferred reactiontemperatures range from 0° C. to 100° C.

Compounds of Formula (3) may be treated with hydrazine-hydrate in thepresence of an inert solvent at temperatures ranging from 0° C. to 200°C., preferably 70° C. to 150° C., to produce compounds of Formula (4).Inert solvents may include, but are not limited to, water, alkylalcohols (1 to 8 carbons, preferably methanol or ethanol), loweralkanenitriles (1 to 6 carbons, preferably acetonitrile), cyclic ethers(preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides(preferably dimethylformamide), N,N-dialkylacetamides (preferablydimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one),dialkylsulfoxides (preferably dimethylsulfoxide) or aromatichydrocarbons (preferably benzene or toluene). Compounds of Formula (4)may be reacted with compounds of Formula (5) (where R^(c) is alkyl (1-6carbons)) in the presence or absence of an acid in the presence of aninert solvent at temperatures ranging from 0° C. to 200° C. to producecompounds of Formula (6). Acids may include, but are not limited toalkanoic acids of 2 to 10 carbons (preferably acetic acid), haloalkanoicacids (2-10 carbons, 1-10 halogens, such as trifluoroacetic acid),arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonicacid), alkanesulfonic acids of 1 to 10 carbons (preferablymethanesulfonic acid), hydrochloric acid, sulfuric acid or phosphoricacid. Stoichiometric or catalytic amounts of such acids may be used.Inert solvents may include, but are not limited to, water,alkanenitriles (1 to 6 carbons, preferably acetonitrile), halocarbons of1 to 6 carbons and 1 to 6 halogens (preferably dichloromethane orchloroform), alkyl alcohols of 1 to 10 carbons (preferably ethanol),dialkyl ethers (4 to 12 carbons, preferably diethyl ether ordi-isopropylether) or cyclic ethers such as dioxan or tetrahydrofuran.Preferred temperatures range from ambient temprature to 100° C.

Compounds of Formula (6) may be converted to intermediate compounds ofFormula (7) by treatment with compounds C═Y(R^(d))₂ (where Y is O or Sand R^(d) is halogen (preferably chlorine), alkoxy (1 to 4 carbons) oralkylthio (1 to 4 carbons)) in the presence or absence of a base in aninert solvent at reaction temperatures from −50° C. to 200° C. Bases mayinclude, but are not limited to, alkali metal hydrides (preferablysodium hydride), alkali metal alkoxides (1 to 6 carbons)(preferablysodium methoxide or sodium ethoxide), alkali metal carbonates, alkalimetal hydroxides, trialkyl amines (preferably N,N-di-isopropyl-N-ethylamine or triethylamine) or aromatic amines (preferably pyridine). Inertsolvents may include, but are not limited to, alkyl alcohols (1 to 8carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6carbons, preferably acetonitrile), cyclic ethers (preferablytetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferablydimethylformamide), N,N-dialkylacetamides (preferablydimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one),dialkylsulfoxides (preferably dimethylsulfoxide) or aromatichydrocarbons (preferably benzene or toluene). Preferred temperatures are0° C. to 150° C.

Intermediate compounds of Formula (7), where Z is N, may be synthesizedaccording the methods outlined in Scheme 5.

Compounds of ArCH₂CN are reacted with compounds of Formula R^(q)CH₂N₃(where R^(q) is a phenyl group optionally substituted by H, alkyl (1 to6 carbons) or alkoxy (1 to 6 carbons) in the presence or absence of abase in an inert solvent at temperatures ranging from 0° C. to 200° C.to generate compounds of Formula (9). Bases may include, but are notlimited to, alkali metal hydrides (preferably sodium hydride), alkalimetal alkoxides (1 to 6 carbons)(preferably sodium methoxide, sodiumethoxide or potassium t-butoxide), alkaline earth metal hydrides, alkalimetal dialkylamides (preferably lithium di-isopropylamide), alkali metalcarbonates, alkali metal hydroxides, alkali metalbis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide),trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine ortriethylamine) or aromatic amines (preferably pyridine). Inert solventsmay include, but are not limited to, alkyl alcohols (1 to 8 carbons,preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons,preferably acetonitrile), dialkyl ethers (preferably diethyl ether),cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane),N,N-dialkylformamides (preferably dimethylformamide),N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides(preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferablydimethylsulfoxide) or aromatic hydrocarbons (preferably benzene ortoluene). Preferred reaction temperatures range from ambient temperatureto 100° C.

Compounds of Formula (9) may be treated with a reducing agent in aninert solvent at −100° C. to 100° C. to afford products of Formula (10).Reducing agents include, but are not limited to, (a) hydrogen gas incombination with noble metal catalysts such as Pd-on-carbon, PtO_(2,)Pt-on-carbon, Rh-on-alumina or Raney nickel, (b) alkali metals(preferably sodium) in combination with liquid ammonia or (c) cericammonium nitrate. Inert solvents may include, but are not limited to,alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), loweralkanenitriles (1 to 6 carbons, preferably acetonitrile), water, dialkylethers (preferably diethyl ether), cyclic ethers (preferablytetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferablydimethylformamide), N,N-dialkylacetamides (preferablydimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one),dialkylsulfoxides (preferably dimethylsulfoxide) or aromatichydrocarbons (preferably benzene or toluene). The preferred reactiontemperatures are −50° C. to 60° C. Compounds of Formula (9) are thenconverted to compounds of Formula (7) (where Z is N) via intermediatesof Formula (11) using the reagents and reaction conditions outlined inScheme 4 for the conversion of compounds of Formula (4) to compounds ofFormula (7) (where Z is CR²).

Compounds of Formula (1) may also be prepared from compounds of Formula(7) (where Y is O, S and Z is defined above) as outlined in Scheme 6:

Compounds of Formula (7) may be reacted with compounds of Formula R³H inthe presence of a dehydrating agent in an inert solvent at reactiontemperatures ranging from 0° C. to 250° C. Dehydrating agents include,but are not limited to, P₂O₅, molecular sieves or inorganic or organicacids. Acids may include, but are not limited to alkanoic acids of 2 to10 carbons (preferably acetic acid), arylsulfonic acids (preferablyp-toluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids of1 to 10 carbons (preferably methanesulfonic acid), hydrochloric acid,sulfuric acid or phosphoric acid. Inert solvents may include, but arenot limited to, alkyl alcohols (1 to 8 carbons, preferably methanol orethanol), lower alkanenitriles (1 to 6 carbons, preferablyacetonitrile), dialkyl ethers (preferably glyme or diglyme), cyclicethers (preferably tetrahydrofuran or 1,4-dioxane),N,N-dialkylformamides (preferably dimethylformamide),N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides(preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferablydimethylsulfoxide), aromatic hydrocarbons (preferably benzene ortoluene) or halocarbons of 1 to 10 carbons and 1 to 10 halogens(preferably chloroform). Preferred reaction temperatures range fromambient temperature to 150° C.

Some compounds of Formula (1) (where A is N) may also be prepared by themethods shown in Scheme 7:

Intermediate compounds of Formula (14), where Z is defined above, may bereacted with compounds of Formula R³C(OR^(e))3, where R^(e) may be alkyl(1 to 6 carbons) in the presence or absence of an acid in an inertsolvent at temperatures ranging from 0° C. to 250° C. Acids may include,but are not limited to alkanoic acids of 2 to 10 carbons (preferablyacetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid orbenzenesulfonic acid), alkanesulfonic acids of 1 to 10 carbons(preferably methanesulfonic acid), hydrochloric acid, sulfuric acid orphosphoric acid. Stoichiometric or catalytic amounts of such acids maybe used. Inert solvents may include, but are not limited to, loweralkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers(preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide),N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides(preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferablydimethylsulfoxide), aromatic hydrocarbons (preferably benzene ortoluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens(preferably dichloromethane). Preferred reaction temperatures range from50° C. to 150° C.

Intermediate compounds of Formula (7) may also be synthesized by thereactions displayed in Scheme 8.

Compounds of Formula (15), (where Y is OH, SH, NR⁶R⁷; Z is definedabove, X is Br, Cl, I, O₃SCF₃ or B(OR″″)₂ and R″″ is H or alkyl (1 to 6carbons)) may be reacted with a compound of Formula ArM (where M ishalogen, alkali metal, ZnCl, ZnBr, ZnI, MgBr, MgCl, MgI, CeCl₂, CeBr₂ orcopper halides) in the presence or absence of an organometallic catalystin the presence or absence of a base in an inert solvents attemperatures ranging from -100° C. to 200° C. Those skilled in the artwill recognize that the reagents ArM may be generated in situ.Organometallic catalysts include, but are not limited to, palladiumphosphine complexes (such as Pd(PPh₃)₄), palladium halides or alkanoates(such as PdCl₂(PPh₃)₂ or Pd(OAc)₂) or nickel complexes (such asNiCl₂(PPh₃)₂). Bases may include, but are not limited to, alkali metalcarbonates or trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amineor triethylamine). Inert solvents may include, but are not limited to,dialkyl ethers (preferably diethyl ether), cyclic ethers (preferablytetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferablydimethylformamide), N,N-dialkylacetamides (preferablydimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one),dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons(preferably benzene or toluene) or water. Preferred reactiontemperatures range from −80° C. to 100° C.

The choices of M and X are known to those skilled in the art (cf.Imamoto, T., Organocerium Reagents in Comprehensive Organic Synthesis,Trost, B. M. ed., (Elmsford, N.Y.: Pergamon Press, 1991), 1, 231-250;Knochel, P., Organozinc, Organocadmium and Organomercury Reagents inComprehensive Organic Synthesis, Trost, B. M. ed., (Elmsford, N.Y.:Pergamon Press, 1991), 1, 211-230; Knight, D. W., Coupling Reactionsbetween sp² Carbon Centers, in Comprehensive Organic Synthesis, Trost,B. M. ed., (Elmsford, N.Y.: Pergamon Press, 1991), 3, 481-520).

Compounds of Formula (1) may also be prepared using he methods shown inScheme 9.

Compounds of Formula (16), where A, Z, R¹ and R³ are defined above and Xis Br, Cl, I, O₃SCF₃ or B(OR″″)₂ and R″″ is H or alkyl (1 to 6 carbons))may be reacted with a compound of Formula ArM (where M is halogen,alkali metal, ZnCl, ZnBr, ZnI, MgBr, MgCl, MgI, CeCl₂, CeBr₂ or copperhalides) in the presence or absence of an organometallic catalyst in thepresence or absence of a base in an inert solvents at temperaturesranging from −100° C. to 200° C. Those skilled in the art will recognizethat the reagents ArM may be generated in situ (see the above referencesin Comprehensive Organic Synthesis). Organometallic catalysts include,but are not limited to, palladium phosphine complexes (such asPd(PPh₃)₄), palladium halides or alkanoates (such as PdCl₂(PPh₃)₂ orPd(OAc)₂) or nickel complexes (such as NiCl₂(PPh₃)₂). Bases may include,but are not limited to, alkali metal carbonates or trialkyl amines(preferably N,N-di-isopropyl-N-ethyl amine or triethylamine). Inertsolvents may include, but are not limited to, dialkyl ethers (preferablydiethyl ether), cyclic ethers (preferably tetrahydrofuran or1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide),N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides(preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferablydimethylsulfoxide), aromatic hydrocarbons (preferably benzene ortoluene) or water. Preferred reaction temperatures range from −80° C. to100° C.

Intermediate compounds of Formula (7)(where Y is O, S, NH, Z is CR² andR¹, R² and Ar are defined as above) may be prepared as illustrated inScheme 10.

Compounds of Formula (3) may be reacted with compounds of FormulaH₂NNH(C═Y)NH₂, where Y is O, S or NH, in the presence or absence of abase or acid in an inert solvent at temperatures from 0° C. to 250° C.to produce compounds of Formula (17). Acids may include, but are notlimited to alkanoic acids of 2 to 10 carbons (preferably acetic acid),arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonicacid), alkanesulfonic acids of 1 to 10 carbons (preferablymethanesulfonic acid), hydrochloric acid, sulfuric acid or phosphoricacid. Stoichiometric or catalytic amounts of such acids may be used.Bases may include, but are not limited to, alkali metal hydrides(preferably sodium hydride), alkali metal alkoxides (1 to 6carbons)(preferably sodium methoxide or sodium ethoxide), alkaline earthmetal hydrides, alkali metal dialkylamides (preferably lithiumdi-isopropylamide), alkali metal bis(trialkylsilyl)amides (preferablysodium bis(trimethylsilyl)amide), trialkyl amines (preferablyN,N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines(preferably pyridine). Inert solvents may include, but are not limitedto, alkyl alcohols (1 to 6 carbons), lower alkanenitriles (1 to 6carbons, preferably acetonitrile), dialkyl ethers (preferably diethylether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane),N,N-dialkylformamides (preferably dimethylformamide),N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides(preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferablydimethylsulfoxide), aromatic hydrocarbons (preferably benzene ortoluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens(preferably dichloromethane).

Preferred reaction temperatures range from 0° C. to 150° C. Compounds ofFormula (17) may then be reacted with compounds of Formula R³C(OR^(e))3,where R^(e) may be alkyl (1 to 6 carbons) in the presence or absence ofan acid in an inert solvent at temperatures ranging from 0° C. to 250°C. Acids may include, but are not limited to alkanoic acids of 2 to 10carbons (preferably acetic acid), arylsulfonic acids (preferablyp-toluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids of1 to 10 carbons (preferably methanesulfonic acid), hydrochloric acid,sulfuric acid or phosphoric acid. Stoichiometric or catalytic amounts ofsuch acids may be used. Inert solvents may include, but are not limitedto, lower alkanenitriles (1 to 6 carbons, preferably acetonitrile),dialkyl ethers (preferably diethyl ether), cyclic ethers (preferablytetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferablydimethylformamide), N,N-dialkylacetamides (preferablydimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one),dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons(preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1to 10 halogens (preferably dichloromethane). Preferred reactiontemperatures range from 50° C. to 150° C.

In Scheme 11, the procedures which may be used to convert compounds ofFormula (1), where R³ is COR⁷, CO₂R⁷, NR⁸COR⁷ and CONR⁶R⁷, to othercompounds of Formula (1), where R³ is CH(OH)R⁷, CH₂OH, NR⁸CH₂R⁷ andCH₂NR⁶R⁷ by treatment with a reducing agent in an inert solvent attemperatures ranging from −80° C. to 250° C.

Reducing agents include, but are not limited to, alkali metal oralkaline earth metal borohydrides (preferably lithium or sodiumborohydride), borane, dialkylboranes (such as di-isoamylborane), alkalimetal aluminum hydrides (preferably lithium aluminum hydride), alkalimetal (trialkoxy)aluminum hydrides, or dialkyl aluminum hydrides (suchas di-isobutylaluminum hydride). Inert solvents may include, but are notlimited to, alkyl alcohols (1 to 6 carbons), dialkyl ethers (preferablydiethyl ether), cyclic ethers (preferably tetrahydrofuran or1,4-dioxane), aromatic hydrocarbons (preferably benzene or toluene).Preferred reaction temperatures range from −80° C. to 100° C.

In Scheme 12, the procedures are shown which may be used to convertcompounds of Formula (1), where R³ is COR⁷ or CO₂R⁷, to other compoundsof Formula (1), where R³ is C(OH)(R⁷)₂ by treatment with a reagent ofFormula R⁷M in an inert solvent at temperatures ranging from −80° C. to250° C.

M is halogen, alkali metal, ZnCl, ZnBr, ZnI, MgBr, MgCl, MgI, CeCl₂,CeBr₂ or copper halides. Inert solvents may include, but are not limitedto, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferablytetrahydrofuran) or aromatic hydrocarbons (preferably benzene ortoluene) . Preferred reaction temperatures range from −80° C. to 100° C.

Compounds of Formula (1), where R³ may be —NR⁸COR⁷, —N(COR⁷)₂,—NR⁸CONR⁶R⁷, —NR⁸CO₂R¹³, —NR⁶R⁷, —NR⁸SO₂R⁷, may be synthesized asdepicted in Scheme 13.

Reaction of compounds of Formula (18), where R and R¹ are defined above,with compounds of Formula (4) or (10) in the presence or absence of basein an inert solvent may produce compounds of Formula (19) attemperatures ranging from −50° C. to 250° C. Bases may include, but arenot limited to, alkali metal hydrides (preferably sodium hydride),alkali metal alkoxides (1 to 6 carbons)(preferably sodium methoxide orsodium ethoxide), alkaline earth metal hydrides, alkali metaldialkylamides (preferably lithium di-isopropylamide), alkali metalcarbonates, alkali metal bis(trialkylsilyl)amides (preferably sodiumbis(trimethylsilyl)amide), trialkyl amines (prefereablydi-isopropylethyl amine) or aromatic amines (preferably pyridine). Inertsolvents may include, but are not limited to, alkyl alcohols (1 to 8carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6carbons, preferably acetonitrile), dialkyl ethers (preferably diethylether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane),N,N-dialkylformamides (preferably dimethylformamide),N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides(preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferablydimethylsulfoxide) or aromatic hydrocarbons (preferably benzene ortoluene). Preferred reaction temperatures range from 0° C. to 100° C.

Compounds of Formula (19) may then be reacted with alkylating agents,sulfonylating agents or acylating agents or sequential reactions withcombinations thereof, in the presence or absence of a base in an inertsolvent at reaction temperatures ranging from −80° C. to 250° C. mayafford compounds of Formula (1), where R³ may be —NR⁸COR⁷, —N(COR⁷)₂,—NR⁸CONR⁶R⁷, —NR⁸CO₂R¹³, —NR⁶R⁷, —NR⁸SO₂R⁷. Alkylating agents mayinclude, but are not limited to, C₁-C₁₀ alkyl -halides, -tosylates,-mesylates or -triflates; C₁-C₁₀ haloalkyl(1-10 halogens)-halides,-tosylates, -mesylates or -triflates; C₂-C₈ alkoxyalkyl-halides,-tosylates, -mesylates or -triflates; C₃-C₆ cycloalkyl-halides,-tosylates, -mesylates or -triflates; C₄-C₁₂ cycloalkylalkyl-halides,-tosylates, -mesylates or -triflates; aryl(C₁-C₄ alkyl)-halides,-tosylates, -mesylates or -triflates; heteroaryl(C₁-C₄ alkyl)-halides,-tosylates, -mesylates or -triflates; or heterocyclyl(C₁-C₄alkyl)-halides, -tosylates, -mesylates or -triflates. Acylating agentsmay include, but are not limited to, C₁ -C₁₀ alkanoyl halides oranhydrides, C₁-C₁₀ haloalkanoyl halides or anhydrides with 1-10halogens, C₂-C₈ alkoxyalkanoyl halides or anhydrides, C₃-C₆cycloalkanoyl halides or anhydrides, C₄-C₁₂ cycloalkylalkanoyl halidesor anhydrides, aroyl halides or anhydrides, aryl(C₁-C₄) alkanoyl halidesor anhydrides, heteroaroyl halides or anhydrides, heteroaryl(C₁-C₄)alkanoyl halides or anhydrides, heterocyclylcarboxylic acid halides oranhydrides or heterocyclyl(C₁-C₄) alkanoyl halides or anhydrides.Sulfonylating agents include, but are not limited to, C₁-C₁₀alkylsulfonyl halides or anhydrides, C₁-C₁₀ haloalkylsulfonyl halides oranhydrides with 1-10 halogens, C₂-C₈ alkoxyalkylsulfonyl halides oranhydrides, C₃-C₆ cycloalkylsulfonyl halides or anhydrides, C₄-C₁₂cycloalkylalkylsulfonyl halides or anhydrides, arylsulfonyl halides oranhydrides, aryl(C₁-C₄ alkyl)-, heteroarylsulfonyl halides oranhydrides, heteroaryl(C₁-C₄ alkyl)sulfonyl halides or anhydrides,heterocyclylsulfonyl halides or anhydrides or heterocyclyl(C₁-C₄alkyl)sulfonyl halides or anhydrides. Bases may include, but are notlimited to, alkali metal hydrides (preferably sodium hydride), alkalimetal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodiumethoxide), alkaline earth metal hydrides, alkali metal dialkylamides(preferably lithium di-isopropylamide), alkali metal carbonates, alkalimetal bis(trialkylsilyl)amides (preferably sodiumbis(trimethylsilyl)amide), trialkyl amines (prefereablydi-isopropylethyl amine) or aromatic amines (preferably pyridine). Inertsolvents may include, but are not limited to, alkyl alcohols (1 to 8carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6carbons, preferably acetonitrile), dialkyl ethers (preferably diethylether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane),N,N-dialkylformamides (preferably dimethylformamide),N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides(preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferablydimethylsulfoxide) or aromatic hydrocarbons (preferably benzene ortoluene). Preferred reaction temperatures range from 0° C. to 100° C.

Compounds of Formula (1), where A is CR and R is defined above, may besynthesized by the methods depicted in Scheme 14.

Compounds of Formula (4) or (10) may be treated with compounds ofFormula (20), where R¹ and R³ are defined above in the presence orabsence of base in an inert solvent at temperatures ranging from 0° C.to 250° C. to give compounds of Formula (1), where A is CR and R isdefined above. Bases may include, but are not limited to, alkali metalhydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6carbons)(preferably sodium methoxide or sodium ethoxide), alkaline earthmetal hydrides, alkali metal dialkylamides (preferably lithiumdi-isopropylamide), alkali metal carbonates, alkali metalbis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide),trialkyl amines (preferably di-isopropylethyl amine) or aromatic amines(preferably pyridine). Inert solvents may include, but are not limitedto, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol),lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkylethers (preferably diethyl ether), cyclic ethers (preferablytetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferablydimethylformamide), N,N-dialkylacetamides (preferablydimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one),dialkylsulfoxides (preferably dimethylsulfoxide) or aromatichydrocarbons (preferably benzene or toluene). Preferred reactiontemperatures range from 0° C. to 100° C. Alternatively, compounds ofFormula (1) where A is CR and R is defined above, may be synthesizedthrough intermediates (22) and (23).

Compounds of Formula (4) or (10) may be treated with compounds ofFormula (21), where R¹ is defined above and R^(e) is alkyl (1-6carbons), in the presence or absence of base in an inert solvent attemperatures ranging from 0° C. to 250° C. to give compounds of Formula(1), where A is CR and R is defined above. Bases may include, but arenot limited to, alkali metal hydrides (preferably sodium hydride),alkali metal alkoxides (1 to 6 carbons)(preferably sodium methoxide orsodium ethoxide), alkaline earth metal hydrides, alkali metaldialkylamides (preferably lithium di-isopropylamide), alkali metalcarbonates, alkali metal bis(trialkylsilyl)amides (preferably sodiumbis(trimethylsilyl)amide), trialkyl amines (prefereablydi-isopropylethyl amine) or aromatic amines (preferably pyridine). Inertsolvents may include, but are not limited to, alkyl alcohols (1 to 8carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6carbons, preferably acetonitrile), dialkyl ethers (preferably diethylether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane),N,N-dialkylformamides (preferably dimethylformamide),N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides(preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferablydimethylsulfoxide) or aromatic hydrocarbons (preferably benzene ortoluene). Preferred reaction temperatures range from 0° C. to 100C.Compounds of Formula (22) may be treated with a halogenating agent orsulfonylating agent in the presence or absence of a base in the presenceor absence of an inert solvent at reaction temperatures ranging from−80° C. to 250° C. to give products of Formula (23) (where X is halogen,alkanesulfonyloxy, arylsulfonyloxy or haloalkane-sulfonyloxy).Halogenating agents include, but are not limited to, SOCl₂, POCl₃, PCl₃,PCl₅, POBr₃, PBr₃ or PBr₅. Sulfonylating agents include, but are notlimited to, alkanesulfonyl halides or anhydrides (such asmethanesulfonyl chloride or methanesulfonic acid anhydride),arylsulfonyl halides or anhydrides (such as p-toluenesulfonyl chlorideor anhydride) or haloalkylsulfonyl halides or anhydrides (preferablytrifluoromethanesulfonic anhydride). Bases may include, but are notlimited to, alkali metal hydrides (preferably sodium hydride), alkalimetal alkoxides (1 to 6 carbons)(preferably sodium methoxide or sodiumethoxide), alkaline earth metal hydrides, alkali metal dialkylamides(preferably lithium di-isopropylamide), alkali metalbis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide),trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine ortriethylamine) or aromatic amines (preferably pyridine). Inert solventsmay include, but are not limited to, lower alkanenitriles (1 to 6carbons, preferably acetonitrile), dialkyl ethers (preferably diethylether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane),N,N-dialkylformamides (preferably dimethylformamide),N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides(preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferablydimethylsulfoxide), aromatic hydrocarbons (preferably benzene ortoluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens(preferably dichloromethane). Preferred reaction temperatures range from−20° C. to 100° C.

Compounds of Formula (23) may be reacted with compounds of Formula R³H(where R3 is defined as above except R³ is not SH, COR⁷, CO₂R⁷, aryl orheteroaryl) in the presence or absence of a base in the presence orabsence of an inert solvent at reaction temperatures ranging from −80°C. to 250° C. to generate compounds of Formula (1). Bases may include,but are not limited to, alkali metal hydrides (preferably sodiumhydride), alkali metal alkoxides (1 to 6 carbons)(preferably sodiummethoxide or sodium ethoxide), alkaline earth metal hydrides, alkalimetal dialkylamides (preferably lithium di-isopropylamide), alkali metalcarbonates, alkali metal bicarbonates, alkali metalbis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide),trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine) or aromaticamines (preferably pyridine). Inert solvents may include, but are notlimited to, alkyl alcohols (1 to 8 carbons, preferably methanol orethanol), lower alkanenitriles (1 to 6 carbons, preferablyacetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers(preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides(preferably dimethylformamide), N,N-dialkylacetamides (preferablydimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one),dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons(preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1to 10 halogens (preferably dichloromethane). Preferred reactiontemperatures range from 0° C. to 140° C.

Some compounds of Formula (1) may also be prepared using the methodsshown in Scheme 15.

A compound of Formula (24) (R_(c) is a lower alkyl group and Ar isdefined as above) may be reacted with hydrazine in the presence orabsence of an inert solvent to afford an intermediate of Formula (25),where Ar is defined as above. The conditions employed are similar tothose used for the preparation of intermediate of Formula (4) fromcompound of Formula (3) in Scheme 4. Compounds of Formula (25), where Ais N, may be reacted with reagents of the formula R¹C(═NH)OR_(e), whereR¹ is defined above and R_(e) is a lower alkyl group) in the presence orabsence of an acid in an inert solvent, followed by reaction with acompound of formula YisC(R_(d))2 (where Y is O or S and R^(d) is halogen(preferably chlorine), alkoxy (1 to 4 carbons) or alkylthio (1 to 4carbons)) in the presence or absence of a base in an inert solvent togive compounds of Formula (27) (where A is N and Y is O, S). Theconditions for these transformations are the same as those employed forthe conversions of compound of Formula (4) to compound of Formula (7) inScheme 4.

Alternatively, compounds of Formula (25), where A is CR, may be reactedwith compounds of the formula R¹(C═O)CHR(C═Y)OR_(c) (where R¹ and R aredefined as above and R_(c) a lower alkyl group) to give a compound ofFormula (27) (where A is CR) using conditions similar to those employedfor the conversion of compounds of Formula (21) to compounds of Formula(22) in Scheme 14. Intermediates of Formula (27) (where Y is O) may betreated with halogenating agents or sulfonylating agents in the presenceor absence of a base in an inert solvent, followed by reaction with R³Hor R²H in the presence or absence of a base in an inert solvent to givecompounds of Formula (1) (where Z is CR²).

It will be recognized by those skilled in the art that variouscombinations of halogenating agents, sulfonylating agents, R³H or R²Hmay be used in different orders of reaction sequences in Scheme 15 toafford compounds of Formula (1). For example, in some cases, it may bedesirable to react compounds with stoichiometric amounts of halogenatingagents or sulfonylating agents, react with R²H (or R³H), then repeat thereaction with halogenating agents or sulfonylating agents and react withR³H (or R²H) to give compounds of Formula (1). The reaction conditionsand reagents used for these conversions are similar to the ones employedfor the conversion of intermediate compounds of Formulae (22) to (23) to(1) in Scheme 14 (for A is CR) or the conversion of intermediatecompounds of Formulae (7) to (8) to (1) in Scheme 1 (where A is N).

Alternatively, compounds of Formula (27) (where Y is S) may be convertedto compounds of Formula (1) in Scheme 15. Intermediate compounds ofFormula (27) may be alkylated with a compound R^(f)X (where R^(f) islower alkyl and X is halogen, alkanesulfonyloxy orhaloalkanesulfonyloxy) in an inert solvent, (then optionally oxidizedwith an oxidizing agent in an inert solvent) and then reacted with R³Hin the presence or absence of a base in an inert solvent to give acompound of Formula (1). The conditions and reagents employed aresimilar to those used in the conversion of intermediate compounds ofFormulae (7) to (12) (or to (13)) to compounds of Formula (1) in Scheme2.

Compounds of Formula (1) may be prepared from compounds of Formula (24),using an alternate route as depicted in Scheme 15. Compounds of Formula(24) may be converted to compounds of Formula (27) via reaction withcompounds of formula NH₂NH(C═NH)NH₂ in the presence or absence of anacid in an inert solvent, followed by reaction with compoundsR¹C(OR_(c))₃ (where R_(c) is lower alkyl and R¹ is defined as above),using the conditions employed for the conversion of compounds ofFormulae (3) to (17) to (7) in Scheme 10.

Some compounds of Formula (2) may be prepared by the methods illustratedin Scheme 16.

Compounds of Formula (27b) may be treated with various alkylating agentsR¹⁴X (where R¹⁴ is defined above and X is halogen, alkanesulfonyloxy orhaloalkanesulfonyloxy) in the presence or absence of a base in an inertsolvent to afford structures of Formula (28). Compounds of Formula (28)(Y is O) may then be converted to compounds of Formula (2) by treatmentwith halogenating agents or sulfonylating agents in the presence orabsence of a base in an inert solvent, followed by reaction with R³H inthe presence or absence of a base in an inert solvent to give compoundsof Formula (2). The reaction conditions used for these conversions aresimilar to the ones employed for the conversion of intermediatecompounds (22) to (23) to (1) in Scheme 14 (for A is CR) or theconversion of intermediate compounds of Formulae (7) to (8) to (1) inScheme 1 (where A is N). Alternatively, compounds of Formula (28) (Y isS) may be alkylated with a compound R^(f)X (where Rf is lower alkyl andX is halogen, alkanesulfonyloxy or haloalkanesulfonyloxy) in an inertsolvent, (then optionally oxidized with an oxidizing agent in an inertsolvent) and then reacted with R³H in the presence or absence of a basein an inert solvent to give a compound of Formula (1). The conditionsand reagents employed are similar to those used in the conversion ofintermediate compounds of Formulae (7) to (12) (or to (13)) to compoundsof Formula (1) in Scheme 2.

Compounds of Formula (1), where Z is COH, may be converted to compoundsof Formula (2) as illustrated in Scheme 16. Treatment with variousalkylating agents R¹⁴X (where R¹⁴ is defined above and X is halogen,alkanesulfonyloxy or haloalkanesulfonyloxy) in the presence or absenceof a base in an inert solvent to afford structures (2). It will berecognized by one skilled in the art that the methods used in Scheme 16may also be used to prepare compounds of Formula (1) where Z is COR⁷.

For Scheme 16, the terms “base” and “inert solvent” may have themeanings given below. Bases may include, but are not limited to, alkalimetal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to6 carbons)(preferably sodium methoxide or sodium ethoxide), alkalineearth metal hydrides, alkali metal dialkylamides (preferably lithiumdi-isopropylamide), alkali metal bis(trialkylsilyl)amides (preferablysodium bis(trimethylsilyl)amide), trialkyl amines (preferablyN,N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines(preferably pyridine). Inert solvents may include, but are not limitedto, lower alkanenitriles (1 to 6 carbons, preferably acetonitrile),dialkyl ethers (preferably diethyl ether), cyclic ethers (preferablytetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferablydimethylformamide), N,N-dialkylacetamides (preferablydimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one),dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons(preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1to 10 halogens (preferably dichloromethane). Preferred reactiontemperatures range from −20° C. to 100° C.

EXAMPLES

Analytical data were recorded for the compounds described below usingthe following general procedures. Proton NMR spectra were recorded on anIBM-Bruker FT-NMR (300 MHz); chemical shifts were recorded in ppm (δ)from an internal tetramethysilane standard in deuterochloroform ordeuterodimethylsulfoxide as specified below. Mass spectra (MS) or highresolution mass spectra (HRMS) were recorded on a Finnegan MAT 8230spectrometer (using chemi-ionization (CI) with NH₃ as the carrier gas orgas chromatography (GC) as specified below) or a Hewlett Packard 5988Amodel spectrometer. Melting points were recorded on a Buchi Model 510melting point apparatus and are uncorrected. Boiling points areuncorrected. All pH determinations during workup were made withindicator paper.

Reagents were purchased from commercial sources and, where necessary,purified prior to use according to the general procedures outlined by D.Perrin and W. L. F. Armarego, Purification of Laboratory Chemicals, 3rded., (New York: Pergamon Press, 1988). Chromatography was performed onsilica gel using the solvent systems indicated below. For mixed solventsystems, the volume ratios are given. Otherwise, parts and percentagesare by weight.

The following examples are provided to describe the invention in furtherdetail. These examples, which set forth the best mode presentlycontemplated for carrying out the invention, are intended to illustrateand not to limit the invention.

EXAMPLE 1 Preparation of2,7-dimethyl-8-(2,4-dimethylphenyl)[1,5-a]-pyrazolo-[1,3,5]-triazin-4(3H)-one(Formula 7, where Y is O, R₁ is CH₃, Z is C—CH₃, Ar is2,4-dimethylphenyl) A. 1-Cyano-1-(2,4-dimethylphenyl)propan-2-one

Sodium pellets (9.8 g, 0.43 mol) were added portionwise to a solution of2,4-dimethylphenylacetonitrile (48 g, 0.33 mol) in ethyl acetate (150mL) at ambient temperature. The reaction mixture was heated to refluxtemperature and stirred for 16 hours. The resulting suspension wascooled to room temperature and filtered. The collected precipitate waswashed with copious amounts of ether and then air-dried. The solid wasdissolved in water and a 1N HCl solution was added until the pH=5-6. Themixture was extracted with ethyl acetate (3×200 mL); the combinedorganic layers were dried over MgSO₄ and filtered. Solvent was removedin vacuo to afford a white solid (45.7 g, 74% yield): NMR (CDCl₃, 300MHz):; CI-MS: 188 (M+H).

B. 5-Amino-4-(2,4-dimethylphenyl)-3-methylpyrazole

A mixture of 1-cyano-1-(2,4-dimethylphenyl)propan-2-one (43.8 g, 0.23mol), hydrazine-hydrate (22 mL, 0.46 mol), glacial acetic acid (45 mL,0.78 mol) and toluene (500 mL) were stirred at reflux temperature for 18hours in an apparatus fitted with a Dean-Stark trap. The reactionmixture was cooled to ambient temperature and solvent was removed invacuo. The residue was dissolved in 6N HCl and the resulting solutionwas extracted with ether three times. A concentrated ammonium hydroxidesolution was added to the aqueous layer until pH=11. The resultingsemi-solution was extracted three times with ethyl acetate. The combinedorganic layers were dried over MgSO₄ and filtered. Solvent was removedin vacuo to give a pale brown viscous oil (34.6 g, 75% yield): NMR(CDCl₃, 300 MHz): 7.10 (s, 1H), 7.05 (d, 2H, J=1), 2.37 (s, 3H), 2.10(s, 3H); CI-MS: 202 (M+H).

C. 5-Acetamidino-4-(2,4-dimethylphenyl)-3-methylpyrazole, acetic acidsalt

Ethyl acetamidate hydrochloride (60 g, 0.48 mol) was added quickly to arapidly stirred mixture of potassium carbonate (69.5 g, 0.50 mol),dichloromethane (120 mL) and water (350 mL). The layers were separatedand the aqueous layer was extracted with dichloromethane (2×120 mL). Thecombined organic layers were dried over MgSO₄ and filtered. Solvent wasremoved by simple distillation and the pot residue, a clear pale yellowliquid, (35.0 g) was used without further purification.

Glacial aetic acid (9.7 mL, 0.17 mol) was added to a stirred mixture of5-amino-4-(2,4-dimethylphenyl)-3-methylpyrazole (34 g, 0.17 mol), ethylacetamidate (22 g, 0.25 mol) and acetonitrile (500 mL). The resultingreaction mixture was stirred at room temperature for 3 days; at the endof which time, it was concentrated in vacuo to about one-third of itsoriginal volume. The resulting suspension was filtered and the collectedsolid was washed with copious amounts of ether. The white solid wasdried in vacuo (31.4 g, 61% yield): NMR (DMSO-d₆, 300 MHz): 7.00 (s,1H), 6.90 (dd, 2H, J=7, 1), 2.28 (s, 3H), 2.08 (s, 3H), 2.00 (s, 3H),1.90 (s, 3H), 1.81 (s, 3H); CI-MS: 243 (M+H).

D.2,7-dimethyl-8-(2,4-dimethylphenyl)[1,5-a]-pyrazolo-[1,3,5]-triazin-4(3H)-one

Sodium pellets (23 g, 1 mol) were added portionwise to ethanol (500 mL)with vigorous stirring. After all the sodium reacted,5-acetamidino-4-(2,4-dimethylphenyl)-3-methylpyrazole, acetic acid salt(31.2 g, 0.1 mol) and diethyl carbonate (97 mL, 0.8 mol) were added. Theresulting reaction mixture was heated to reflux temperature and stirredfor 18 hours. The mix was cooled to room temperature and solvent wasremoved in vacuo. The residue was dissolved in water and a 1N HClsolution was added slowly until pH=5-6. The aqueous layer was extractedwith ethyl acetate three times; the combined organic layers were driedover MgSO₄ and filtered. Solvent was removed in vacuo to give a pale tansolid (26 g, 98% yield): NMR (CDCl₃, 300 MHz): 7.15(s, 1H), 7.09 (s,2H), 2.45 (s, 3H), 2.39 (s, 3H), 2.30 (s, 3H); CI-MS: 269 (M+H).

EXAMPLE 2 Preparation of5-methyl-3-(2,4,6-trimethylphenyl)[1,5-a]-[1,2,3]-triazolo-[1,3,5]-triazin-7(6H)-one(Formula 7, where Y is O, R₁ is CH₃, Z is N, Ar is2,4,6-trimethylphenyl) A.1-Phenylmethyl-4-(2,4,6-trimethylphenyl)-5-aminotriazole

A mixture of 2,4,6-trimethylbenzyl cyanide (1.0 g, 6.3 mmol), benzylazide (0.92 g, 6.9 mmol) and potassium t-butoxide (0.78 g, 6.9 mmol) intetrahydrofuran (10 mL) was stirred at ambient temperature for 2.5 days.The resulting suspension was diluted with water and extracted threetimes with ethyl acetate. The combined organic layers were dried overMgSO₄ and filtered. Solvent was removed in vacuo to give a brown oil.Trituration with ether and filtration afforded a yellow solid (1.12 g,61% yield): NMR (CDCl₃, 300 MHz):7.60-7.30 (m, 5H), 7.30-7.20 (m, 2H),5.50 (s, 2H), 3.18 (br s, 2H), 2.30 (s, 3H), 2.10 (s, 6H); CI-MS: 293(M+H).

B. 4-(2,4,6-Trimethylphenyl)-5-aminotriazole

Sodium (500 mg, 22 mmol) was added with stirring to a mixture of liquidammonia (30 mL) and1-phenylmethyl-4-(2,4,6-trimethylphenyl)-5-aminotriazole (1.1 g, 3.8mmol). The reaction mixture was stirred until a dark green colorpersisted. An ammonium chloride solution (mL) was added and the mixturewas stirred while warming to ambient temperature over 16 hours. Theresidue was treated with a 1M HCl solution and filtered. The aqueouslayer was basified with a concentrated ammonium hydroxide solution(pH=9) and then extracted with ethyl acetate three times. The combinedorganic layers were dried over MgSO₄ and filtered. Solvent was removedin vacuo to give a yellow solid (520 mg), which was homogeneous by thinlayer chromatography (ethyl acetate):

NMR (CDCl₃, 300 MHz): 6.97 (s, 2H), 3.68-3.50 (br.s, 2H), 2.32 (s, 3H),2.10 (s, 6H); CI-MS: 203 (M+H).

C. 4-(2,4,6-Trimethylphenyl)-5-acetamidinotriazole, acetic acid salt

A mixture of 4-(2,4,6-trimethylphenyl)-5-aminotriazole (400 mg, 1.98mmol), ethyl acetamidate 261 mg, 3 mmol) and glacial acetic acid (0.1mL, 1.98 mmol) in acetonitrile (6 mL) was stirred at ambient temperaturefor 4 hours. The resulting suspension was filtered and the collectedsolid was washed with copious amounts of ether. Drying in vacuo affordeda white solid (490 mg, 82% yield): NMR (DMSO-d₆, 300 MHz):7.90-7.70 (brs, 0.5H), 7.50-7.20 (br. s, 0.5H), 6.90 (s, 2H), 6.90 (s, 2H), 3.50-3.10(br s, 3H), 2.30-2.20 (br s, 3H), 2.05 (d, 1H, J=7), 1.96 (s, 6H), 1.87(s, 6H); CI-MS: 244 (M+H).

D. 5-methyl-3-(2,4,6-trimethylphenyl)[1,5-a]-[1,2,3]-triazolo-[1,3,5]-triazin-7(4H)-one

Sodium (368 mg, 16.2 mmol) was added with stirring to ethanol (10 mL) atroom temperature. After the sodium had reacted,4-(2,4,6-trimethylphenyl)-5-acetamidino-triazole, acetic acid salt (490mg, 1.6 mmol) and diethyl carbonate (1.6 mL, 13 mmol) were added. Thereaction mixture was stirred at reflux temperature for 5 hours, thencooled to room temperature. The reaction mixture was diluted with water;a 1N HCl solution was added until pH=5-6 and three extractions withethyl acetate were performed. The combined organic layers were driedover MgSO₄ and filtered. Solvent was removed in vacuo to give a yellowresidue. Trituration with ether and filtration afforded a yellow solid(300 mg, 69% yield): NMR (CDCl₃, 300 MHz): 6.98 (s, 2H), 2.55 (s, 3H),2.35 (s, 3H), 2.10 (s, 6H); CI-MS: 270 (M+H).

EXAMPLE 3 Preparation of4-(di(carbomethoxy)methyl)-2,7-dimethyl-8-(2,4-dimethylphenyl)[1,5-a]-pyrazolo-1,3,5-triazine(Formula 1, where R³ is CH(CHCO₂CH₃)₂, R₁ is CH₃, Z is C—CH₃, Ar is2,4-dimethylphenyl) A.4-chloro-2,7-dimethyl-8-(2,4-dichlorophenyl)[1,5-a]-pyrazolotriazine

A mixture of2,7-dimethyl-8-(2,4-dimethylphenyl)[1,5-a]-pyrazolo-1,3,5-triazin-4-one(Example 1, 1.38 g, 4.5 mmol), N,N-dimethylaniline (1 mL, 8 mmol) andphosphorus oxychloride (10 mL) was stirred at reflux temperature for 48hours. The excess phosphorus oxychloride was removed in vacuo. Theresidue was poured onto ice-water, stirred briefly and extracted quicklywith ethyl acetate three times. The combined organic layers were washedwith ice water, then dried over MgSO₄ and filtered. Solvent was removedin vacuo to give a brown oil. Flash column chromatography (ethylacetate:hexanes::1:4) gave one fraction (Rf=0.5) Solvent was removed invacuo to afford a yellow oil (1.0 g, 68% yield): NMR (CDCl₃, 300 MHz):7.55 (d, 1H, J=1), 7.38 (dd, 1H, J=7,1), 7.30 (d, 1H, J=7), 2.68 (s,3H), 2.45 (s, 3H); CI-MS: 327 (M+H).

B.4-(di(carbomethoxy)methyl)-2,7-dimethyl-8-(2,4-dimethylphenyl)[1,5-a]-pyrazolo-1,3,5-triazine

Sodium hydride (60% in oil, 80 mg, 2 mmol) was washed with hexanestwice, decanted after each washing and taken up in anhydroustetrahydrofuran (THF, 1 mL). A solution of diethyl malonate (0.32 g, 2mmol) in THF (2 mL) was added dropwise over 5 min, during which timevigorous gas evolution ensued. A solution of4-chloro-2,7-dimethyl-8-(2,4-dichlorophenyl)[1,5-a]pyrazolotriazine (0.5g, 1.75 mmol) in THF (2 mL) was added and the reaction mixture was thenstirred under a nitrogen atmosphere for 48 hours. The resultingsuspension was poured onto water and extracted three times with ethylacetate. The combined organic layers were washed once with brine, driedover MgSO₄ and filtered. Solvent was removed in vacuo to give a brownoil. Column chromatography (ethyl acetate:hexanes::1:9) afforded, afterremoval of solvent in vacuo, a pale yellow solid (Rf=0.2, 250 mg, 35%yield): mp 50-52° C.; NMR (CDCl₃, 300 MHz): 12.35 (br.s, 1H, 7.15-7.00(m, 3H), 4.40 (q, 2H, J=7), 4.30 (q, 2H, J=7), 2.4, 2.35, 2.3, 2.2, 2.1(5 s, 12H), 1.4 (t, 3H, J=7), 1.35-1.25 (m, 3H); CI-HRMS: Calcd:411.2032, Found: 411.2023.

EXAMPLE 6 Preparation of4-(1,3-dimethoxy-2-propylamino)-2,7-dimethyl-8-(2,4-dichlorophenyl)[1,5-a]-pyrazolo-1,3,5-triazine(Formula 1, where R³ is NHCH(CH₂OCH₃)₂ R₁ is CH₃, Z is C—CH₃, Ar is2,4-dichlorophenyl) A.4-chloro-2,7-dimethyl-8-(2,4-dichlorophenyl)[1,5-a]-pyrazolotriazine

A mixture of 2,7-dimethyl-8-(2,4dimethylphenyl)[1,5-a]-pyrazolo-1,3,5-triazin-4-one (Example 1, 1.38 g,4.5 mmol), N,N-dimethylaniline (1 mL, 8 mmol) and phosphorus oxychloride(10 mL) was stirred at reflux temperature for 48 hours. The excessphosphorus oxychloride was removed in vacuo. The residue was poured ontoice-water, stirred briefly and extracted quickly with ethyl acetatethree times. The combined organic layers were washed with ice water,then dried over MgSO₄ and filtered. Solvent was removed in vacuo to givea brown oil. Flash column chromatography (ethyl acetate:hexanes::1:4)gave one fraction (Rf=0.5) Solvent was removed in vacuo to afford ayellow oil (1.0 g, 68% yield): NMR (CDCl₃, 300 MHz): 7.55 (d, 1H, J=1),7.38 (dd, 1H, J=7,1), 7.30 (d, 1H, J=7), 2.68 (s, 3H), 2.45 (s, 3H);CI-MS: 327 (M+H).

B.4-(1,3-dimethoxy-2-propylamino)-2,7-dimethyl-8-(2,4-dichlorophenyl)[1,5-a]-pyrazolo-1,3,5-triazine

A mixture of4-chloro-2,7-dimethyl-8-(2,4-dichlorophenyl)[1,5-a]-pyrazolo-1,3,5-triazine(Part A, 570 mg, 1.74 mmol), 1,3-dimethoxypropyl-2-aminopropane (25 mg,2.08 mmol) and ethanol (10 mL) was stirred at ambient temperature for 18hours. The reaction mixture was poured onto water (25 mL) and extractedthree times with ethyl acetate. The combined organic layers were driedover MgSO₄ and filtered. Solvent was removed in vacuo. Columnchromatography (CH₂Cl₂:CH₃OH::50:1) afforded one fraction. Removal ofsolvent in vacuo gave a solid (250 mg, 35% yield): mp 118-120° C.; NMR(CDCl₃, 300 MHz): 7.50 (s, 1H), 7.28 (dd, 2H, J=8,1), 6.75 (d, 1H, J=8),4.70-4.58 (m, 1H), 3.70-3.55 (m, 4H), 3.43 (s, 6H), 2.50 (s, 3H), 2.35(s, 3H); CI-HRMS: Calcd: 409.1072, Found: 409.1085; Analysis Calcd. forC₁₈H₂₁Cl₂N₅O₂: C, 52.69; H, 5.17; N, 17.07; Cl, 17.28; Found: C, 52.82;H, 5.06; N, 16.77; Cl, 17.50.

Using the above procedures and modifications known to one skilled in theart of organic synthesis, the following additional examples of Tables1-4 may be prepared.

The examples delineated in TABLE 1 may be prepared by the methodsoutlined in Examples 1, 2, 3 or 6. Commonly used abbreviations are: Phis phenyl, Pr is propyl, Me is methyl, Et is ethyl, Bu is butyl, Ex isExample.

TABLE 1

Ex. Z R₃ Ar mp (° C.)  6^(a) C-Me NHCH(CH₂OMe)₂ 2,4-Cl₂-Ph 118-120 7^(b) C-Me NHCHPr₂ 2,4-Cl₂-Ph 114-116  8^(c) C-Me NEtBU 2,4-Cl₂-Ph oil 9^(d) C-Me NPr(CH₂-c-C₃H₅) 2,4-Cl₂-Ph oil  10^(e) C-Me N(CH₂CH₂OMe)₂2,4-Cl₂-Ph oil  11^(f) C-Me NH-3-heptyl 2,4-Cl₂-Ph 90-92  12^(g) C-MeNHCH(Et)CH₂OMe 2,4-Cl₂-Ph 179-181  13^(h) C-Me NEt₂ 2,4-Cl₂-Ph 133-134 14^(i) C-Me NHCH(CH₂OEt)₂ 2,4-Cl₂-Ph oil  15^(j) C-Me NH-3-pentyl2,4-Cl₂-Ph 139-140  16^(k) C-Me NMePh 2,4-Cl₂-Ph 60-62  17^(l) C-Me NPr₂2,4-Cl₂-Ph oil  18^(m) C-Me NH-3-hexyl 2,4-Cl₂-Ph 130-132  19 C-Memorpholino 2,4-Cl₂-Ph  20 C-Me N(CH₂Ph)CH₂CH₂OMe 2,4-Cl₂-Ph  21 C-MeNHCH(CH₂Ph)CH₂OMe 2,4-Cl₂-Ph  22 C-Me NH-4-tetrahydropyranyl 2,4-Cl₂-Ph 23 C-Me NH-cyclopentyl 2,4-Cl₂-Ph  24 C-Me 1,2,3,4-tetrahydro-2,4-Cl₂-Ph isoquinolinyl  25 C-Me CH₂-(1,2,3,4-tetrahydro- 2,4-Cl₂-Ph  isoquinolinyl)  26 C-Me OEt 2,4-Cl₂-Ph 141-143  27 C-Me OCH(Et)CH₂OMe2,4-Cl₂-Ph  28 C-Me OCH₂Ph 2,4-Cl₂-Ph  29 C-Me O-3-pentyl 2,4-Cl₂-Ph  30C-Me SEt 2,4-Cl₂-Ph  31 C-Me S(O)Et 2,4-Cl₂-Ph  32 C-Me SO₂Et 2,4-Cl₂-Ph 33 C-Me CH(CO₂Et)₂ 2,4-Cl₂-Ph  34 C-Me C(Et)(CO₂Et)₂ 2,4-Cl₂-Ph  35C-Me CH(Et)CH₂OH 2,4-Cl₂-Ph  36 C-Me CH(Et)CH₂OMe 2,4-Cl₂-Ph  37 C-MeCONMe₂ 2,4-Cl₂-Ph  38 C-Me COCH₃ 2,4-Cl₂-Ph  39 C-Me CH(OH)CH₃2,4-Cl₂-Ph  40 C-Me C(OH)Ph-3-pyridyl 2,4-Cl₂-Ph  41 C-Me Ph 2,4-Cl₂-Ph 42 C-Me 2-CF₃-Ph 2,4-Cl₂-Ph  43 C-Me 2-Ph-Ph 2,4-Cl₂-Ph  44 C-Me3-pentyl 2,4-Cl₂-Ph  45 C-Me cyclobutyl 2,4-Cl₂-Ph  46 C-Me 3-pyridyl2,4-Cl₂-Ph  47 C-Me CH(Et)CH₂CONMe₂ 2,4-Cl₂-Ph  48 C-Me CH(Et)CH₂CH₂NMe₂2,4-Cl₂-Ph  49^(o) C-Me NHCH(CH₂OMe)₂ 2,4,6-Me₃-Ph 125-127  50 C-MeNHCHPr₂ 2,4,6-Me₃-Ph  51 C-Me NEtBu 2,4,6-Me₃-Ph  52 C-MeNPr(CH₂-c-C₃H₅) 2,4,6-Me₃-Ph  53^(ae) C-Me N(CH₂CH₂OMe)₂ 2,4,6-Me₃-Ph123-124  54 C-Me NH-3-heptyl 2,4,6-Me₃-Ph  55^(ac) C-Me NHCH(Et)CH₂OMe2,4,6-Me₃-Ph 145-146  56^(ah) C-Me NEt₂ 2,4,6-Me₃-Ph 88-90  57^(ai) C-MeNHCH(CH₂OEt)₂ 2,4,6-Me₃-Ph 132-134  58^(ad) C-Me NH-3-pentyl2,4,6-Me₃-Ph 134-135  59 C-Me NMePh 2,4,6-Me₃-Ph  60 C-Me NPr₂2,4,6-Me₃-Ph  61 C-Me NH-3-hexyl 2,4,6-Me₃-Ph  62 C-Me morpholino2,4,6-Me₃-Ph  63 C-Me N(CH₂Ph)CH₂CH₂OMe 2,4,6-Me₃-Ph  64 C-MeNHCH(CH₂Ph)CH₂OMe 2,4,6-Me₃-Ph  65 C-Me NH-4-tetrahydropyranyl2,4,6-Me₃-Ph  66 C-Me NH-cyclopentyl 2,4,6-Me₃-Ph  67 C-Me1,2,3,4-tetrahydro- 2,4,6-Me₃-Ph isoquinolinyl  68 C-MeCH₂-(1,2,3,4-tetrahydro- 2,4,6-Me₃-Ph   isoquinolinyl)  69 C-Me OEt2,4,6-Me₃-Ph  70 C-Me OCH(Et)CH₂OMe 2,4,6-Me₃-Ph  71 C-Me OCH₂Ph2,4,6-Me₃-Ph  72 C-Me O-3-pentyl 2,4,6-Me₃-Ph  73 C-Me SEt 2,4,6-Me₃-Ph 74 C-Me S(O)Et 2,4,6-Me₃-Ph  75 C-Me SO₂Et 2,4,6-Me₃-Ph  76 C-MeCH(CO₂Et)₂ 2,4,6-Me₃-Ph  77 C-Me C(Et)(CO₂Et)₂ 2,4,6-Me₃-Ph  78 C-MeCH(Et)CH₂OH 2,4,6-Me₃-Ph  79 C-Me CH(Et)CH₂OMe 2,4,6-Me₃-Ph  80 C-MeCONMe₂ 2,4,6-Me₃-Ph  81 C-Me COCH₃ 2,4,6-Me₃-Ph  82 C-Me CH(OH)CH₃2,4,6-Me₃-Ph  83 C-Me C(OH)Ph-3-pyridyl 2,4,6-Me₃-Ph  84 C-Me Ph2,4,6-Me₃-Ph  85 C-Me 2-CF₃-Ph 2,4,6-Me₃-Ph  86 C-Me 2-Ph-Ph2,4,6-Me₃-Ph  87 C-Me 3-pentyl 2,4,6-Me₃-Ph  88 C-Me cyclobutyl2,4,6-Me₃-Ph  89 C-Me 3-pyridyl 2,4,6-Me₃-Ph  90 C-Me CH(Et)CH₂CONMe₂2,4,6-Me₃-Ph  91 C-Me CH(Et)CH₂CH₂NMe₂ 2,4,6-Me₃-Ph  92^(p) C-MeNHCH(CH₂OMe)₂ 2,4-Me₂-Ph 44-45  93^(q) C-Me N(CH₂CH₂OMe)₂ 2,4-Me₂-Ph oil 94^(r) C-Me NHCH(Et)CH₂OMe 2,4-Me₂-Ph 102-104  95^(s) C-Me NH-3-pentyl2,4-Me₂-Ph 102-104  96^(t) C-Me NEt₂ 2,4-Me₂-Ph oil  97^(u) C-MeN(CH₂CN)₂ 2,4-Me₂-Ph 148-150  98^(v) C-Me NHCH(Me)CH₂OMe 2,4-Me₂-Ph102-104  99^(w) C-Me OCH(Et)CH₂OMe 2,4-Me₂-Ph oil 100^(x) C-MeNPr-c-C₃H₅ 2,4-Me₂-Ph oil 101^(y) C-Me NHCH(Me)CH₂NMe₂ 2,4-Me₂-Ph 47-48102^(z) C-Me N(c-C₃H₅)CH₂CH₂CN 2,4-Me₂-Ph 117-118 103^(aa) C-MeN(Pr)CH₂CH₂CN 2,4-Me₂-Ph oil 104^(ab) C-Me N(Bu)CH₂CH₂CN 2,4-Me₂-Ph oil105 C-Me NHCHPr₂ 2,4-Me₂-Ph 106 C-Me NEtBu 2,4-Me₂-Ph 107 C-MeNPr(CH₂-c-C₃H₅) 2,4-Me₂-Ph 108 C-Me NH-3-heptyl 2,4-Me₂-Ph 109 C-Me NEt₂2,4-Me₂-Ph 110 C-Me NHCH(CH₂OEt)₂ 2,4-Me₂-Ph 111 C-Me NH-3-pentyl2,4-Me₂-Ph 112 C-Me NMePh 2,4-Me₂-Ph 113 C-Me NPr₂ 2,4-Me₂-Ph 114 C-MeNH-3-hexyl 2,4-Me₂-Ph 115 C-Me morpholino 2,4-Me₂-Ph 116 C-MeN(CH₂Ph)CH₂CH₂OMe 2,4-Me₂-Ph 117 C-Me NHCH(CH₂Ph)CH₂OMe 2,4-Me₂-Ph 118C-Me NH-4-tetrahydropyranyl 2,4-Me₂-Ph 119 C-Me NH-cyclopentyl2,4-Me₂-Ph 120 C-Me 1,2,3,4-tetrahydro- 2,4-Me₂-Ph isoquinolinyl 121C-Me CH₂-(1,2,3,4-tetrahydro- 2,4-Me₂-Ph isoquinolinyl) 122 C-Me OEt2,4-Me₂-Ph 123 C-Me OCH(Et)CH₂OMe 2,4-Me₂-Ph 124 C-Me OCH₂Ph 2,4-Me₂-Ph125 C-Me O-3-pentyl 2,4-Me₂-Ph 126 C-Me SEt 2,4-Me₂-Ph 127 C-Me S(O)Et2,4-Me₂-Ph 128 C-Me SO₂Et 2,4-Me₂-Ph  3 C-Me CH(CO₂Et)₂ 2,4-Me₂-Ph 50-52129 C-Me C(Et)(CO₂Et)₂ 2,4-Me₂-Ph 130 C-Me CH(Et)CH₂OH 2,4-Me₂-Ph 131C-Me CH(Et)CH₂OMe 2,4-Me₂-Ph 132 C-Me CH(Et)CH₂COEt 2,4-Me₂-Ph 133 C-MeCONMe₂ 2,4-Me₂-Ph 134 C-Me COCH₃ 2,4-Me₂-Ph 135 C-Me CH(OH)CH₃2,4-Me₂-Ph 136 C-Me C(OH)Ph-3-pyridyl 2,4-Me₂-Ph 137 C-Me Ph 2,4-Me₂-Ph138 C-Me 2-CF₃-Ph 2,4-Me₂-Ph 139 C-Me 2-Ph-Ph 2,4-Me₂-Ph 140 C-Me3-pentyl 2,4-Me₂-Ph 141 C-Me cyclobutyl 2,4-Me₂-Ph 142 C-Me 3-pyridyl2,4-Me₂-Ph 143 C-Me CH(Et)CH₂CONMe₂ 2,4-Me₂-Ph 144 C-Me CH(Et)CH₂CH₂NMe₂2,4-Me₂-Ph 145^(bc) C-Me NHCH(CH₂OMe)₂ 2-Me-4-MeO-Ph 45-46 146^(bd) C-MeN(CH₂CH₂OMe)₂ 2-Me-4-MeO-Ph oil 147^(be) C-Me NHCH(Et)CH₂OMe2-Me-4-MeO-Ph 86-88 148^(bf) C-Me N(Pr)CH₂CH₂CN 2-Me-4-MeO-Ph oil 149C-Me OCH(Et)CH₂OMe 2-Me-4-MeO-Ph 150^(af) C-Me NHCH(CH₂OMe)₂2-Br-4-MeO-Ph 88-90 151^(al) C-Me N(CH₂CH₂OMe)₂ 2-Br-4-MeO-Ph oil152^(ag) C-Me NHCH(Et)CH₂OMe 2-Br-4-MeO-Ph 95-97 153 C-Me N(Pr)CH₂CH₂CN2-Br-4-MeO-Ph 154 C-Me OCH(Et)CH₂OMe 2-Br-4-MeO-Ph 155 C-MeNHCH(CH₂OMe)₂ 2-Me-4-NMe₂-Ph 156 C-Me N(CH₂CH₂OMe)₂ 2-Me-4-NMe₂-Ph oil157 C-Me NHCH(Et)CH₂OMe 2-Me-4-NMe₂-Ph 158 C-Me N(Pr)CH₂CH₂CN2-Me-4-NMe₂-Ph 159 C-Me OCH(Et)CH₂OMe 2-Me-4-NMe₂-Ph 160 C-MeNHCH(CH₂OMe)₂ 2-Br-4-NMe₂-Ph 161 C-Me N(CH₂CH₂OMe)₂ 2-Br-4-NMe₂-Ph 162C-Me NHCH(Et)CH₂OMe 2-Br-4-NMe₂-Ph 163 C-Me N(Pr)CH₂CH₂CN 2-Br-4-NMe₂-Ph164 C-Me OCH(Et)CH₂OMe 2-Br-4-NMe₂-Ph 165 C-Me NHCH(CH₂OMe)₂2-Br-4-i-Pr-Ph 166 C-Me N(CH₂CH₂OMe)₂ 2-Br-4-i-Pr-Ph 167 C-MeNHCH(Et)CH₂OMe 2-Br-4-i-Pr-Ph 168 C-Me N(Pr)CH₂CH₂CN 2-Br-4-i-Pr-Ph 169C-Me OCH(Et)CH₂OMe 2-Br-4-i-Pr-Ph 170 C-Me NHCH(CH₂OMe)₂ 2-Br-4-Me-Ph171 C-Me N(CH₂CH₂OMe)₂ 2-Br-4-Me-Ph 172 C-Me NHCH(Et)CH₂OMe 2-Br-4-Me-Ph173 C-Me N(Pr)CH₂CH₂CN 2-Br-4-Me-Ph 174 C-Me OCH(Et)CH₂OMe 2-Br-4-Me-Ph175^(ar) C-Me NHCH(CH₂OMe)₂ 2-Me-4-Br-Ph 108-109 176 C-Me N(CH₂CH₂OMe)₂2-Me-4-Br-Ph 177 C-Me NHCH(Et)CH₂OMe 2-Me-4-Br-Ph 178 C-Me N(Pr)CH₂CH₂CN2-Me-4-Br-Ph 179 C-Me OCH(Et)CH₂OMe 2-Me-4-Br-Ph 180 C-Me NHCH(CH₂OMe)₂2-Cl-4,6-Me₂-Ph 181 C-Me N(CH₂CH₂OMe)₂ 2-Cl-4,6-Me₂-Ph 182 C-MeNHCH(CH₂OMe)₂ 4-Br-2,6-(Me)₂-Ph 183 C-Me N(CH₂CH₂OMe)₂ 4-Br-2,6-(Me)₂-Ph184 C-Me NHCH(CH₂OMe)₂ 4-i-Pr-2-SMe-Ph 185 C-Me N(CH₂CH₂OMe)₂4-i-Pr-2-SMe-Ph 186 C-Me NHCH(CH₂OMe)₂ 2-Br-4-CF₃-Ph 187 C-MeN(CH₂CH₂OMe)₂ 2-Br-4-CF₃-Ph 188 C-Me NHCH(CH₂OMe)₂ 2 Br-4,6-(MeO)₂-Ph189 C-Me N(CH₂CH₂OMe)₂ 2-Br-4,6-(MeO)₂-Ph 190 C-Me NHCH(CH₂OMe)₂ 2Cl-4,6-(MeO)₂-Ph 191 C-Me N(CH₂CH₂OMe)₂ 2-Cl-4,6-(MeO)₂-Ph 192 C-MeNHCH(CH₂OMe)₂ 2,6-(Me)₂-4-SMe-Ph 193 C-Me N(CH₂CH₂OMe)₂2,6-(Me)₂-4-SMe-Ph 194 C-Me NHCH(CH₂OMe)₂ 4-(COMe)-2-Br-Ph 195 C-MeN(CH₂CH₂OMe)₂ 4-(COMe)-2-Br-Ph 196 C-Me NHCH(CH₂OMe)₂2,4,6-Me₃-pyrid-3-yl 197 C-Me N(CH₂CH₂OMe)₂ 2,4,6-Me₃-pyrid-3-yl 198C-Me NHCH(CH₂OMe)₂ 2,4-(Br)₂-Ph 199 C-Me N(CH₂CH₂OMe)₂ 2,4-(Br)₂-Ph 200C-Me NHCH(CH₂OMe)₂ 4-i-Pr-2-SMe-Ph 201 C-Me N(CH₂CH₂OMe)₂4-i-Pr-2-SMe-Ph 202 C-Me NHCH(CH₂OMe)₂ 4-i-Pr-2-SO₂Me-Ph 203 C-MeN(CH₂CH₂OMe)₂ 4-i-Pr-2-SO₂Me-Ph 204 C-Me NHCH(CH₂OMe)₂2,6-(Me)₂-4-SMe-Ph 205 C-Me N(CH₂CH₂OMe)₂ 2,6-(Me)₂-4-SMe-Ph 206 C-MeNHCH(CH₂OMe)₂ 2,6-(Me)₂-4-SO₂Me-Ph 207 C-Me N(CH₂CH₂OMe)₂2,6-(Me)₂-4-SO₂Me-Ph 208 C-Me NHCH(CH₂OMe)₂ 2-I-4-i-Pr-Ph 209 C-MeN(CH₂CH₂OMe)₂ 2-I-4-i-Pr-Ph 210 C-Me NHCH(CH₂OMe)₂2-Br-4-N(Me)₂-6-MeO-Ph 211 C-Me N(CH₂CH₂OMe)₂ 2-Br-4-N(Me)₂-6-MeO-Ph 212C-Me NHCH(CH₂OMe)₂ 2,4-[SMe]2-Ph 213 C-Me N(CH₂CH₂OMe)₂ 2,4-[SMe]2-Ph214 C-Me NHCH(CH₂OMe)₂ 2,4-[SO₂Me]2-Ph 215 C-Me N(CH₂CH₂OMe)₂2,4-[SO₂Me]2-Ph 216 C-Me NHCH(CH₂OMe)₂ 4-i-Pr-2-SMe-Ph 217 C-MeN(CH₂CH₂OMe)₂ 4-i-Pr-2-SMe-Ph 218 C-Me NHCH(CH₂OMe)₂ 4-i-Pr-2-SO₂Me-Ph219 C-Me N(CH₂CH₂OMe)₂ 4-i-Pr-2-SO₂Me-Ph 220 C-Me NHCH(CH₂OMe)₂2-N(Me)₂-4-Me-Ph 221 C-Me N(CH₂CH₂OMe)₂ 2-N(Me)₂-4-Me-Ph 222 C-MeNHCH(CH₂OMe)₂ 2-MeS-4,6-(Me)₂-Ph 223 C-Me N(CH₂CH₂OMe)₂2-MeS-4,6-(Me)₂-Ph 224 C-Me NHCH(CH₂OMe)₂ 2-(CH₃CO)-4,6-(Me)₂-Ph 225C-Me N(CH₂CH₂OMe)₂ 2-(CH₃CO)-4,6-(Me)₂-Ph 226 H NHCH(CH₂OMe)₂ 2,4-Me₂-Ph227 H NHCH(CH₂OMe)₂ 2,4-Me₂-Ph 228 CF3 N(CH₂CH₂OMe)₂ 2,4-Me₂-Ph 229 CF3N(CH₂CH₂OMe)₂ 2,4-Me₂-Ph 230 N NHCH(CH₂OMe)₂ 2,4,6-Me₃-Ph 231 N NHCHPr₂2,4,6-Me₃-Ph 232 N NEtBU 2,4,6-Me₃-Ph 233 N NPr(CH₂-c-C₃H₅) 2,4,6-Me₃-Ph234 N N(CH₂CH₂OMe)₂ 2,4,6-Me₃-Ph 235 N NH-3-heptyl 2,4,6-Me₃-Ph 236 NNHCH(Et)CH₂OMe 2,4,6-Me₃-Ph 237 N NEt₂ 2,4,6-Me₃-Ph 238 N NHCH(CH₂OEt)₂2,4,6-Me₃-Ph 239 N NH-3-pentyl 2,4,6-Me₃-Ph 240 N NMePh 2,4,6-Me₃-Ph 241N NPr₂ 2,4,6-Me₃-Ph 242 N NH-3-hexyl 2,4,6-Me₃-Ph 243 N morpholino2,4,6-Me₃-Ph 244 N N(CH₂Ph)CH₂CH₂OMe 2,4,6-Me₃-Ph 245 NNHCH(CH₂Ph)CH₂OMe 2,4,6-Me₃-Ph 246 N NH-4-tetrahydropyranyl 2,4,6-Me₃-Ph247 N NH-cyclopentyl 2,4,6-Me₃-Ph 248 N 1,2,3,4-tetrahydro- 2,4,6-Me₃-Phisoquinolinyl 249 N CH₂-(1,2,3,4-tetrahydro- 2,4,6-Me₃-Ph isoquinolinyl)250 N OEt 2,4,6-Me₃-Ph 251 N OCH(Et)CH₂OMe 2,4,6-Me₃-Ph 252 N OCH₂Ph2,4,6-Me₃-Ph 253 N O-3-pentyl 2,4,6-Me₃-Ph 254 N SEt 2,4,6-Me₃-Ph 255 NS(O)Et 2,4,6-Me₃-Ph 256 N SO₂Et 2,4,6-Me₃-Ph 257 N CH(CO₂Et)₂2,4,6-Me₃-Ph 258 N C(Et)(CO₂Et)₂ 2,4,6-Me₃-Ph 259 N CH(Et)CH₂OH2,4,6-Me₃-Ph 260 N CH(Et)CH₂OMe 2,4,6-Me₃-Ph 261 N CONMe₂ 2,4,6-Me₃-Ph262 N COCH₃ 2,4,6-Me₃-Ph 263 N CH(OH)CH₃ 2,4,6-Me₃-Ph 264 NC(OH)Ph-3-pyridyl 2,4,6-Me₃-Ph 265 N Ph 2,4,6-Me₃-Ph 266 N 2-CF₃-Ph2,4,6-Me₃-Ph 267 N 2-Ph-Ph 2,4,6-Me₃-Ph 268 N 3-pentyl 2,4,6-Me₃-Ph 269N cyclobutyl 2,4,6-Me₃-Ph 270 N 3-pyridyl 2,4,6-Me₃-Ph 271 NCH(Et)CH₂CONMe₂ 2,4,6-Me₃-Ph 272 N CH(Et)CH₂CH₂NMe₂ 2,4,6-Me₃-Ph 273 NNHCH(CH₂OMe)₂ 2,4-Me₂-Ph 274 N NHCHPr₂ 2,4-Me₂-Ph 275 N NEtBU 2,4-Me₂-Ph276 N NPr(CH₂-c-C₃H₅) 2,4-Me₂-Ph 277 N N(CH₂CH₂OMe)₂ 2,4-Me₂-Ph 278 NNH-3-heptyl 2,4-Me₂-Ph 279 N NHCH(Et)CH_(2OMe) 2,4-Me₂-Ph 280 N NEt₂2,4-Me₂-Ph 281 N NHCH(CH₂OEt)₂ 2,4-Me₂-Ph 282 N NH-3-pentyl 2,4-Me₂-Ph283 N NMePh 2,4-Me₂-Ph 284 N NPr₂ 2,4-Me₂-Ph 285 N NH-3-hexyl 2,4-Me₂-Ph286 N morpholino 2,4-Me₂-Ph 287 N N(CH₂Ph)CH₂CH₂OMe 2,4-Me₂-Ph 288 NNHCH(CH₂Ph)CH₂OMe 2,4-Me₂-Ph 289 N NH-4-tetrahydropyranyl 2,4-Me₂-Ph 290N NH-cyclopentyl 2,4-Me₂-Ph 291 N 1,2,3,4-tetrahydro- 2,4-Me₂-Phisoquinolinyl 292 N CH₂-(1,2,3,4-tetrahydro- 2,4-Me₂-Ph isoquinolinyl)293 N OEt 2,4-Me₂-Ph 294 N OCH(Et)CH₂OMe 2,4-Me₂-Ph 295 N OCH₂Ph2,4-Me₂-Ph 296 N O-3-pentyl 2,4-Me₂-Ph 297 N SEt 2,4-Me₂-Ph 298 N S(O)Et2,4-Me₂-Ph 299 N SO₂Et 2,4-Me₂-Ph 300 N CH(CO₂Et)₂ 2,4-Me₂-Ph 301 NC(Et)(CO₂Et)₂ 2,4-Me₂-Ph 302 N CH(Et)CH₂OH 2,4-Me₂-Ph 303 N CH(Et)CH₂OMe2,4-Me₂-Ph 304 N CONMe₂ 2,4-Me₂-Ph 305 N COCH₃ 2,4-Me₂-Ph 306 NCH(OH)CH₃ 2,4-Me₂-Ph 307 N C(OH)Ph-3-pyridyl 2,4-Me₂-Ph 308 N Ph2,4-Me₂-Ph 309 N 2-CF₃-Ph 2,4-Me₂-Ph 310 N 2-Ph-Ph 2,4-Me₂-Ph 311 N3-pentyl 2,4-Me₂-Ph 312 N cyclobutyl 2,4-Me₂-Ph 313 N 3-pyridyl2,4-Me₂-Ph 314 N CH(Et)CH₂CONMe₂ 2,4-Me₂-Ph 315 N CH(Et)CH₂CH₂NMe₂2,4-Me₂-Ph 316^(an) C-Me NEt₂ 2-Br-4-MeO-Ph oil 317^(am) C-MeNH-3-pentyl 2-Br-4-MeO-Ph oil 318^(aj) C-Me NHCH(CH₂CH₂OMe)CH₂OMe2,4,6-Me₃-Ph 101-103 319^(ao) C-Me NH(c-C₃H₅) 2,4-Me₂-Ph oil 320^(ak)C-Me morpholino 2,4,6-Me₃-Ph 139-141 321^(ap) C-Me NHCH(CH₂OMe)₂2-CN-4-Me-Ph 152-153 322^(aq) C-Me N(c-C₃H₅)CH₂CH₂CN 2,4,6-Me₃-Ph149-151 324^(as) C-Me NHCH(CH₂CH₂OMe)CH₂OMe 2-Me-4-Br-Ph 115-117325^(at) C-Me NHCH(CH₂OMe)₂ 2,5-Me₂-4-MeO-Ph 55-57 326^(au) C-MeN(CH₂CH₂OMe)₂ 2,5-Me₂-4-MeO-Ph 72 327^(av) C-Me NH-3-pentyl2,5-Me₂-4-MeO-Ph 45-47 328^(aw) C-Me NEt₂ 2,5-Me₂-4-MeO-Ph oil 329^(ax)C-Me NHCH(CH₂OMe)₂ 2-Cl-4-MePh 80-81 330^(ay) C-Me NCH(Et)CH₂OMe2-Cl-4-MePh 77-79 331^(az) C-Me N(CH₂CH₂OMe)₂ 2-Cl-4-MePh oil 332^(ba)C-Me (S)—NHCH(CH₂CH₂OMe)CH₂OMe 2-Cl-4-MePh 139-140 333^(bb) C-MeN(c-C₃H₅)CH₂CH₂CN 2,5-Me₂-4-MeOPh 120-122 334^(bg) C-Me NEt₂2-Me-4-MeOPh oil 335^(bh) C-Me OEt 2-Me-4-MeOPh oil 336^(bi) C-Me(S)—NHCH(CH₂CH₂OMe)CH₂OMe 2-Me-4-MeOPh oil 337^(bj) C-MeN(c-C₃H₅)CH₂CH₂CN 2-Me-4-MeOPh 129 338^(bk) C-Me NHCH(CH₂CH₂OEt)₂2-Me-4-MeOPh amorph. 339 C-Me N(c-C₃H₅)CH₂CH₂CN 2,4-Cl₂-Ph 109-110 340C-Me (S)—NHCH(CH₂CH₂OMe)CH₂OMe 2,4-Cl₂-Ph 93-94 341 C-Me NH-3-pentyl2-Me-4-BrPh 118-119 342 C-Me N(CH₂CH₂OMe)₂ 2-Me-4-BrPh oil 343 C-MeNHCH(CH₂-iPr)CH₂OMe 2,4-Me₂-Ph oil 344 C-Me NHCH(Pr)CH₂OMe 2,4-Me₂-Ph94-95 345 C-Me NHCH(Et)CH₂OEt 2,4-Me₂-Ph 76-77 346 C-MeNHCH(CH₂OMe)CH₂CH₂OMe 2-Me-4-Me₂NPh oil 347 C-Me NEt₂ 2-Me-4-ClPh oil348 C-Me NH-3-pentyl 2-Me-4-ClPh 122-124 349 C-Me N(CH₂CH₂OMe)₂2-Me-4-ClPh oil 350 C-Me NHCH(CH₂OMe)₂ 2-Me-4-ClPh 122-123 351 C-Me NEt₂2-Me-4-ClPh oil 352 C-Me NEt₂ 2-Cl-4-MePh oil 353 C-Me NH-3-pentyl2-Cl-4-MePh 120-121 354 C-Me NHCH(CH₂OMe)₂ 2-Cl-4-MeOPh 355^(bl) C-MeN(CH₂CH₂OMe)₂ 2-Cl-4-MeOPh oil 356^(bm) C-Me NHCH(Et)CH₂OMe 2-Cl-4-MeOPh108-110 357^(bn) C-Me N(c-Pr)CH₂CH₂CN 2-Cl-4-MeOPh 127-129 358^(bo) C-MeNEt₂ 2-Cl-4-MeOPh oil 359^(bp) C-Me NH-3-pentyl 2-Cl-4-MeOPh 77-79 360C-Me NHCH(Et)CH₂CH₂OMe 2-Cl-4-MeOPh 361 C-Me NHCH(Me)CH₂CH₂OMe2-Cl-4-MeOPh 362 C-Me NHCH(Et)CH₂CH₂OMe 2-Br-4-MeOPh 363 C-MeNHCH(Me)CH₂CH₂OMe 2-Br-4-MeOPh 364 C-Me NHCH(Et)CH₂CH₂OMe 2-Me-4-MeOPh365 C-Me NHCH(Me)CH₂CH₂OMe 2-Me-4-MeOPh 366 C-Me NHCH(CH₂OMe)₂2-Cl-4,5-(MeO)₂Ph 367 C-Me N(CH₂CH₂OMe)₂ 2-Cl-4,5-(MeO)₂Ph 368 C-MeNHCH(Et)CH₂OMe 2-Cl-4,5-(MeO)₂Ph 369 C-Me N(c-Pr)CH₂CH₂CN2-Cl-4,5-(MeO)₂Ph 370 C-Me NEt₂ 2-Cl-4,5-(MeO)₂Ph 371 C-Me NH-3-pentyl2-Cl-4,5-(MeO)₂Ph 372 C-Me NHCH(Et)CH₂CH₂OMe 2-Cl-4,5-(MeO)₂Ph 373 C-MeNHCH(Me)CH₂CH₂OMe 2-Cl-4,5-(MeO)₂Ph 374^(bq) C-Me NHCH(CH₂OMe)₂2-Br-4,5-(MeO)₂Ph 137-138 375 C-Me N(CH₂CH₂OMe)₂ 2-Br-4,5-(MeO)₂Ph376^(br) C-Me NHCH(Et)CH₂OMe 2-Br-4,5-(MeO)₂Ph 147-148 377 C-MeN(c-Pr)CH₂CH₂CN 2-Br-4,5-(MeO)₂Ph 378^(bs) C-Me NEt₂ 2-Br-4,5-(MeO)₂Ph52-58 379 C-Me NH-3-pentyl 2-Br-4,5-(MeO)₂Ph 380 C-Me NHCH(Et)CH₂CH₂OMe2-Br-4,5-(MeO)₂Ph 381 C-Me NHCH(Me)CH₂CH₂OMe 2-Br-4,5-(MeO)₂Ph 382 C-MeNHCH(CH₂OMe)₂ 2-Cl-4,6-(MeO)₂Ph 383 C-Me N(CH₂CH₂OMe)₂ 2-Cl-4,6-(MeO)₂Ph384 C-Me NHCH(Et)CH₂OMe 2-Cl-4,6-(MeO)₂Ph 385 C-Me N(c-Pr)CH₂CH₂CN2-Cl-4,6-(MeO)₂Ph 386 C-Me NEt₂ 2-Cl-4,6-(MeO)₂Ph 387 C-Me NH-3-pentyl2-Cl-4,6-(MeO)₂Ph 388 C-Me NHCH(Et)CH₂CH₂OMe 2-Cl-4,6-(MeO)₂Ph 389 C-MeNHCH(Me)CH₂CH₂OMe 2-Cl-4,6-(MeO)₂Ph 390 C-Me NHCH(CH₂OMe)₂2-Me-4,6-(MeO)₂Ph 391 C-Me N(CH₂CH₂OMe)₂ 2-Me-4,6-(MeO)₂Ph 392 C-MeNHCH(Et)CH₂OMe 2-Me-4,6-(MeO)₂Ph 393 C-Me N(c-Pr)CH₂CH₂CN2-Me-4,6-(MeO)₂Ph 395 C-Me NEt₂ 2-Me-4,6-(MeO)₂Ph 396 C-Me NH-3-pentyl2-Me-4,6-(MeO)₂Ph 397 C-Me NHCH(Et)CH₂CH₂OMe 2-Me-4,6-(MeO)₂Ph 398 C-MeNHCH(Me)CH₂CH₂OMe 2-Me-4,6-(MeO)₂Ph 399 C-Me N(c-Pr)CH₂CH₂CN2-Br-4,6-(MeO)₂Ph 400 C-Me NEt₂ 2-Br-4,6-(MeO)₂Ph 401 C-Me NH-3-pentyl2-Br-4,6-(MeO)₂Ph 402 C-Me NHCH(Et)CH₂CH₂OMe 2-Br-4,6-(MeO)₂Ph 403 C-MeNHCH(Me)CH₂CH₂OMe 2-Br-4,6-(MeO)₂Ph 404 C-Me NHCH(Et)CH₂CH₂OMe2-Me-4-MeOPh 405 C-Me NHCH(Me)CH₂CH₂OMe 2-Me-4-MeOPh 406 C-MeNHCH(CH₂OMe)₂ 2-MeO-4-MePh 407 C-Me N(CH₂CH₂OMe)₂ 2-MeO-4-MePh 408 C-MeNHCH(Et)CH₂OMe 2-MeO-4-MePh 409 C-Me N(c-Pr)CH₂CH₂CN 2-MeO-4-MePh 410C-Me NEt₂ 2-MeO-4-MePh 411 C-Me NH-3-pentyl 2-MeO-4-MePh 412 C-MeNHCH(Et)CH₂CH₂OMe 2-MeO-4-MePh 413 C-Me NHCH(Me)CH₂CH₂OMe 2-MeO-4-MePh414 C-Me NHCH(CH₂OMe)₂ 2-MeO-4-MePh 415 C-Me N(CH₂CH₂OMe)₂ 2-MeO-4-MePh416 C-Me NHCH(Et)CH₂OMe 2-MeO-4-MePh 417 C-Me N(c-Pr)CH₂CH₂CN2-MeO-4-MePh 418 C-Me NEt₂ 2-MeO-4-MePh 419 C-Me NH-3-pentyl2-MeO-4-MePh 420 C-Me NHCH(Et)CH₂CH₂OMe 2-MeO-4-MePh 421 C-MeNHCH(Me)CH₂CH₂OMe 2-MeO-4-MePh 423^(bt) C-Me NHCH(CH₂OMe)₂ 2-MeO-4-ClPhoil 424 C-Me N(CH₂CH₂OMe)₂ 2-MeO-4-ClPh 425 C-Me NHCH(Et)CH₂OMe2-MeO-4-ClPh 426 C-Me N(c-Pr)CH₂CH₂CN 2-MeO-4-ClPh 427 C-Me NEt₂2-MeO-4-ClPh 428 C-Me NH-3-pentyl 2-MeO-4-ClPh 429 C-MeNHCH(Et)CH₂CH₂OMe 2-MeO-4-ClPh 430 C-Me NHCH(Me)CH₂CH₂OMe 2-MeO-4-ClPh

Notes for Table 1:

a) Analysis Calcd: C, 52.69; H, 5.17; N, 17.07; Cl, 17.28; Found: C,52.82; H, 5.06; N, 16.77; Cl, 17.50.

b) CI-HRMS: Calcd: 406.1565, Found: 405.1573 (M+H);

Analysis Calcd: C, 59.11; H, 6.20; N, 17.23; Cl, 17.45; Found: C, 59.93;H, 6.34; N, 16.50; Cl, 16.95;

NMR (CDCl₃, 300 MHz): 0.95 (t, J=8, 4H), 1.30-1.40 (m, 4H), 1.50-1.75(m, 4H), 2.35 (s, 3H), 2.48 (s, 3H), 4.30-4.45 (m, 1H), 6.15 (d, J=8,1H), 7.30 (s, 2H), 7.50 (s, 1H)

c) CI-HRMS: Calcd: 392.1409, Found: 392.1388 (M+H);

NMR (CDCl₃, 300 MHz): 1.00 (t, J=8, 3H), 1.35 (t, J=8, 3H), 1.41 (q,J=8, 2H), 1.65-1.85 (m, 2H), 2.30 (s, 3H), 2.40 (s, 3H), 3.85-4.20 (m,4H), 7.30 (s, 2H), 7.50 (s, 1H).

d) CI-HRMS: Calcd: 404.1409, Found: 404.1408 (M+H);

NMR(CDCl₃, 300 MHz): 0.35-0.45 (m, 2H), 0.52-0.62 (m, 2H), 0.98 (t, J=8,3H), 1.70-1.90 (m, 2H), 2.30 (s, 3H), 2.40 (s, 3H), 3.85-4.02 (m, 2H),4.02-4.20 (m, 2H), 7.30 (s, 2H), 7.50 (s, 1H)

e) CI-HRMS: Calcd: 424.1307, Found: 424.1307 (M+H):

NMR (CDCl₃, 300 MHz): 2.28 (s, 3H), 2.40 (s, 3H), 3.40 (s, 6H), 3.75 (t,J=8, 4H), 4.20-4.45 (m, 4H), 7.30 (s, 2H), 7.50 (s, 1H).

f) CI-HRMS: Calcd: 406.1565, Found: 406.1578 (M+H);

NMR (CDCl₃, 300 MHz): 0.90 (t, J=8, 3H), 1.00 (t, J=8, 3H), 1.28-1.45(m, 4H), 1.50-1.80 (m, 4H), 2.35 (s, 3H), 2.50 (s, 3H), 4.20-4.35 (m,1H), 6.10-6.23 (m, 1H), 7.30 (s, 2H), 7.50 (s, 1H).

g) CI-HRMS: Calcd: 394.1201, Found: 394.1209 (M+H);

NMR (CDCl₃, 300 MHz): 1.02 (t, J=8, 3H), 1.65-1.90 (m, 2H), 2.35 (s,3H), 2.48 (s, 3H), 3.40 (s, 3H), 3.50-3.60 (m, 2H), 4.35-4.45 (brs, 1H),6.50-6.60 (m, 1H), 7.30 (s, 2H), 7.50 (s, 1H).

h) CI-HRMS: Calcd: 364.1096, Found: 364.1093 (M+H);

Analysis: Calcd: C, 56.05; H, 5.27; N, 19.23; Cl, 19.46; Found: C,55.96; H, 5.24; N, 18.93; Cl, 19.25;

NMR (CDCl₃, 300 MHz): 1.35 (t, J 8, 6H), 2.30 (3, 3H), 2.40 (s, 3H),3.95-4.15 (m, 4H), 7.30 (s, 2H), 7.50 (d, J=1, 1H).

i) CI-HRMS: Calcd: 438.1464, Found: 438.1454 (M+H);

NMR (CDCl₃, 300 MHz): 1.22 (t, J=8, 6H), 2.35 (s, 3H), 2.47 (s, 3H),3.39 (q, J=8, 4H), 3.65 (dd, J=8, 1, 2H), 3.73 (dd, J=8, 1, 2H),4.55-4.65 (m, 1H), 6.75 (d, J=8, 1H), 7.30 (d, J=1, 2H), 7.50 (s, 1H).

j) CI-HRMS: Calcd: 378.1252, Found: 378.1249 (M+H);

Analysis: Calcd: C, 57.15; H, 5.61; N, 18.51; Cl, 18.74; Found: C,57.56; H, 5.65; N, 18.35; Cl, 18.45;

NMR (CDCl₃, 300 MHz): 1.00 (t, J=8, 6H), 1.55-1.70 (m, 2H), 1.70-1.85(m, 2H), 2.35 (s, 3H), 2.50 (s, 3H), 4.15-4.25 (m, 1H), 6.18 (d, J=8,1H), 7.30 (s, 2H), 7.50 (s, 1H).

k) CI-HRMS: Calcd: 398.0939, Found: 398.0922 (M+H);

Analysis: Calcd: C, 60.31; H, 4.30; N, 17.58; Cl, 17.80; Found: C,60.29; H, 4.59; N, 17.09; Cl, 17.57;

NMR (CDCl₃, 300 MHz): 2.05 (s, 3H), 2.50 (s, 3H), 3.78 (s, 3H),7.20-7.45 (m, 7H), 7.50 (d, J=1, 1H).

l) CI-HRMS: Calcd: 392.1409, Found: 392.1391 (M+H);

NMR (CDCl₃, 300 MHz): 0.98 (t, J=8, 6H), 1.70-1.85 (m, 4H), 2.30 (s,3H), 2.40 (s, 3H), 3.80-4.10 (m, 4H), 7.30 (s, 2H), 7.50 (d, J=1, 1H).

m) CI-HRMS: Calcd: 392.1409, Found: 392.1415 (M+H);

Analysis: Calcd: C, 58.17; H, 5.92; N, 17.85; Cl, 18.07; Found: C,58.41; H, 5.85: N, 18.10; Cl, 17.75;

NMR (CDCl₃, 300 MHz): 0.90-1.05 (m, 6H), 1.35-1.55 (m, 2H), 1.55-1.85(m, 4H), 2.35 (s, 3H), 2.48 (s, 3H), 4.20-4.35 (m, 1H), 6.15 (d, J=8,1H), 7.30 (s, 2H), 7.50 (d, J=1, 1H).

n) CI-HRMS: Calcd: 337.0623, Found: 337.0689 (M+H);

Analysis: Calcd: C, 53.43; H, 4.18; N, 16.62; Cl, 21.03, Found: C,53.56; H, 4.33; N, 16.56; Cl, 20.75;

NMR (CDCl₃, 300 MHz): 1.60 (t, J=8, 3H), 2.40 (s, 3H), 2.55 (s, 3H),4.80 (q, J=8, 2H), 7.30 (d, J=8, 1H), 7.35 (dd, J=8, 1, 1H), 7.55 (d,J=1, 1H)

o) CI-HRMS: Calcd: 383.2321, Found: 383.2309 (M+H);

NMR (CDCl₃, 300 MHz): 2.00 (s, 6H), 2.20 (s, 3H), 2.30 (s, 3H), 2.45 (s,3H), 3.45 (s, 6H), 3.61 (dd, J=8, 8, 2H), 3.70 (dd, J=8, 8, 2H),4.60-4.70 (m, 1H), 6.70 (d, J=8, 1H), 6.94 (s, 2H).

p) CI-HRMS: Calcd: 370.2243, Found: 370.2246 (M+H);

Analysis: Calcd: C, 65.02; H, 7.38; N, 18.96;

Found: C, 65.22; H, 7.39; N, 18.71;

NMR (CDCl₃, 300 MHz): 2.18 (s, 3H), 2.30 (s, 3H), 2.45 (s, 3H), 3.45 (s,6H), 3.60 (dd, J=8, 8, 2H), 3.69 (dd, J=8, 8, 2H), 4.60-4.70 (m, 1H),6.70 (d, J=8, 1H), 7.05 (d, J=8, 1H), 7.07 (d, J=8, 1H), 7.10 (s, 1H).

q) CI-HRMS: Calcd: 384.2400, Found: 384.2393 (M+H);

NMR (CDCl₃, 300 MHz): 2.16 (s, 3H), 2.25 (s, 3H), 2.35 (s, 3H), 2.39 (s,3H), 3.40 (s, 6H), 3.77 (t, J=8, 4H), 4.20-4.45 (m, 4H), 7.02 (d, J=8,1H) 7.05 (s, 1H), 7.10 (d, J=7, 1H).

r) CI-HRMS: Calcd: 354.2294, Found: 354.2271 (M+H);

Analysis: Calcd: C, 67.96; H, 7.71; N, 19.81;

Found: C, 67.56; H, 7.37; N, 19.60;

NMR (CDCl₃, 300 MHz): 1.03 (t, J=8, 3H), 1.65-1.88 (m, 2H), 2.17 (s,3H), 2.30 (s, 3H), 2.35 (s, 3H), 2.45 (s, 3H), 3.40 (s, 3H), 3.50-3.62(m, 2H), 4.30-4.45 (m, 1H), 6.51 (d, J=8, 1H), 7.04 (d, J=8, 1H), 7.10(d, J=8, 1H), 7.12 (s, 1H).

s) CI-HRMS: Calcd: 338.2345, Found: 338.2332 (M+H);

Analysis: Calcd: C, 71.18; H, 8.06; N, 20.75;

Found: C, 71.43; H, 7.80; N, 20.70;

NMR (CDCl₃, 300 MHz): 1.00 (t, J=8, 6H), 1.55-1.70 (m, 2H), 1.70-1.85(m, 2H), 2.19 (s, 3H), 2.30 (s, 3H), 2.35 (s, 3H), 2.46 (s, 3H),4.15-4.26 (m, 1H), 6.17 (d, J=8, 1H), 7.06 (d, J=8, 1H), 7.10 (d, J=1,1H), 7.13 (s, 1H).

t) CI-HRMS: Calcd: 324.2188, Found: 324.2188 (M+H);

NMR (CDCl₃, 300 MHz): 1.25 (t, J=8, 6H), 2.16 (s, 3H), 2.28 (s, 3H),2.35 (s, 3H), 2.40 (s, 3H), 3.95-4.20 (m, 4H), 7.05 (dd, J=8, 1, 1H),7.07 (s, 1H), 7.10 (d, J=1, 1H)

u) CI-HRMS: Calcd: 346.1780, Found: 346.1785 (M+H);

Analysis: Calcd: C, 66.07; H, 5.54; N, 28.39;

Found: C, 66.07; H, 5.60; N, 27.81;

NMR (CDCl₃, 300 MHz): 2.15 (s, 3H), 2.32 (s, 3H) 2.17 (s, 3H), 2.52 (s,3H), 5.25-5.35 (m, 4H), 7.08 (s, 2H), 7.15 (s, 1H).

v) CI-HRMS: Calcd: 340.2137, Found: 340.2137 (M+H);

Analysis: Calcd: C, 67.23; H, 7.42; N, 20.63;

Found:C, 67.11; H, 7.39; N, 20.26;

NMR (CDCl₃, 300 MHz): 1.40 (d, J=8, 3H), 2.16 (s, 3H), 2.32 (s, 3H),2.35 (s, 3H), 2.47 (s, 3H), 3.42 (s, 3H), 3.50-3.60 (m, 2H), 4.50-4.15(m, 1H), 6.56 (d, J=8, 1H), 7.00-7.15 (m, 3H).

w) CI-HRMS: Calcd: 355.2134, Found: 355.2134 (M+H);

NMR (CDCl₃, 300 MHz): 1.05 (t, J=8, 3H), 1.85-2.00 (m, 2H), 2.17 (s,3H), 2.36 (s, 6H), 2.50 (s, 3H), 3.41 (s, 3H), 3.45 (dd, J=8, 3, 1H),3.82 (dd, J=8, 1, 1H), 5.70-5.80 (m, 1H), 7.00-7.20 (m, 3H).

x) CI-HRMS: Calcd: 364.2501, Found: 364.2501 (M+H);

NMR (CDCl₃, 300 MHz): 0.35-0.43 (m, 2H), 0.50-0.60 (m, 2H), 0.98 (t,J=8, 3H), 1.20-1.30 (m, 1H), 1.72-1.90 (m, 2H), 2.18 (s, 3H) 2.28 (s,3H), 2.35 (s, 3H), 2.40 (s, 3H), 3.88-4.03 (m, 2H), 4.03-4.20 (m, 2H),7.00-7.15 (m, 3H).

y) CI-HRMS: Calcd: 353.2454, Found: 353.2454 (M+H);

Analysis: Calcd: C, 68.15; H, 8.02; N, 23.84;

Found: C, 67.43; H, 7.81; N, 23.45;

NMR (CDCl₃, 300 MHz): 1.38 (d, J=8, 3H), 2.18 (s, 3H), 2.30-2.40 (m,12H), 2.47 93, 3H), 2.60-2.75 (m, 2H), 4.30-4.50 (m, 1H), 6.60-6.70 (m,1H), 7.00-7.15 (m, 3H).

z) CI-HRMS: Calcd: 361.2140, Found: 361.2128 (M+H);

NMR (CDCl₃, 300 MHz): 0.75-0.83 (m, 2H), 1.00-1.10 (m, 2H), 2.17 (s,3H), 2.30 (s, 3H), 2.36 (s, 3H), 2.47 (s, 3H), 2.85 (t, J=8, 2H),3.30-3.40 (m, 1H), 4.40-4.55 (m, 2H), 7.00-7.18 (m, 3H).

aa) CI-HRMS: Calcd: 363.2297, Found: 363.2311 (M+H);

NMR (CDCl₃, 300 MHz): 1.01 (t, 3H, J=8), 1.75-1.90 (m,2H), 2.15 (s,3H),2.19 (s, 3H), 2.35 (s, 3H), 2.40 (s, 3H), 2.40 (s, 3H), 2.98 (t, 2H,J=8), 3.97-4.15 (m, 2H), 4.15-4.30 (m, 2H), 7.03(d, 1H, 1H), 7.08 (d,1H, J=8), 7.10 (s, 1H).

ab) CI-HRMS: Calcd: 363.2297, Found: 363.2295 (M+H);

NMR (CDCl₃, 300 MHz): 1.01 (t, 3H, J=8), 1.35-1.55 (m, 2H), 1.75-1.90(m, 2H), 2.15 (s, 3H), 2.30 (s, 3H), 2.36 (s, 3H), 2.46 (s, 3H),4.10-4.30 (m, 2H), 4.95-5.10 (br s, 2H), 7.05 (d, 1H, J=8), 7.10 (d, 1H,J=8), 7.15 (s, 1H).

ac) CI-HRMS: Calcd: 368.2450, Found: 368.2436;

Analysis: Calcd: C, 68.62; H, 7.95; N, 19.06;

Found: C, 68.73; H, 7.97; N, 19.09; NMR (CDCl₃, 300 MHz): 1.05 (t, J=8,3H), 1.70-1.90 (m, 2H), 2.01 (d, J=3, 6H), 2.20 (s, 3H), 2.30 (s, 3H),2.46, 2.465 (s, s, 3H), 3.42, 3.48 (s, s, 3H), 3.53-3.63 (m, 2H),4.35-4.45 (m, 1H), 6.73 (d, J=8, 1H), 6.97 (s, 2H).

(ad) CI-HRMS: Calcd: 352.2501, Found: 352.2500 (M+H): Analysis: Calcd:C, 71.76; H, 8.33; N, 19.92, Found: C, 71.55; H, 8.15; N, 19.28;

NMR (CDCl₃, 300 MHz): 1.01 (t, J=8, 6H), 1.58-1.70 (m, 2H), 1.70-1.85(m, 2H), 2.02 (s, 6H), 2.19 (s, 3H), 2.45 (s, 3H), 4.12-4.28 (m, 1H),6.18 (d, J=8, 1H), 6.95 (s, 2H).

(ae) CI-HRMS: Calcd: 398.2556, Found: 398.2551 (M+H); Analysis: Calcd:C, 66.47; H, 7.86; N, 17.62, Found: C, 66.74; H, 7.79; N, 17.70;

NMR (CDCl₃, 300 MHz): 2.00 (s, 6H), 2.12 (s, 3H), 2.30 (s, 3H), 2.37 (s,3H), 3.40 (s, 6H), 3.78 (t, J=8, 4H), 4.25-4.40 (m, 4H), 6.93 (s, 2H).

(af) CI-HRMS: Calcd: 450.1141, Found: 450.1133 (M+H);

Analysis: Calcd: C, 50.67; H, 5.37; N, 15.55; Br, 17.74; Found: C,52.36; H, 5.84; N, 14.90; Br, 17.44;

NMR (CDCl₃, 300 MHz): 2.32 (s, 3H), 2.57 (s, 3H), 3.42 (s, 6H), 3.60 (q,J=8, 2H), 3.69 (q, J=8, 2H), 3.82 (s, 3H), 4.60-4.70 (m, 1H), 6.73 (d,J=8, 1H), 6.93 (dd, J=8, 1, 1H), 7.22 (d, J=8, 1H).

ag) CI-HRMS: Calcd: 434.1192, Found: 434.1169 (M+H);

Analysis: Calcd: C, 52.54; H, 5.58; N, 16.12; Br, 18.40; Found: C,52.57; H, 5.60; N, 15.98; Br, 18.22;

NMR (CDCl₃, 300 MHz): 1.00-1.07 (m, 3H), 1.65-1.85 (m, 2H), 2.35 (s,3H), 2.46, 2.47 (s, s, 3H), 3.40, 3.45 (s, s, 3H), 3.83 (s, 3H),4.35-4.45 (m, 1H), 6.55 (d, J=8, 1H), 6.92 (dd, J=8, 1, 1H), 7.20-7.30(m, 2H).

ah) CI-HRMS: Calcd: 337.2266, Found: 337.2251 (M+H);

Analysis: Calcd: C, 70.18; H, 8.06; N, 20.75;

Found: C, 70.69; H, 7.66; N, 20.34;

NMR (CDCl₃, 300 MHz): 1.35 (t, J=8, 6H), 2.01 (s, 6H), 2.15 (s, 3H),2.30 (s, 3H), 2.38 (s, 3H), 4.07 (q, J=8, 4H), 6.93 (s, 2H)

ai) CI-HRMS: Calcd: 412.2713, Found: 412.2687 (M+H);

Analysis: Calcd: C, 67.13; H, 8.08; N, 17.02;

Found : C, 67.22; H, 7.85; N, 17.13;

NMR (CDCl₃, 300 MHz):1.24 (t, J=8, 6H), 2.00 (s, 6H), 2.20 (s, 3H), 2.30(s, 3H), 2.43 (s, 3H), 3.60 (q, J=8, 4H), 3.66 (dd, J=8, 3, 2H), 3.75(dd, J=8, 3, 2H), 4.55-4.65 (m, 1H), 6.75 (d, J=8, 1H), 6.95 (s, 2H).

aj) CI-HRMS: Calcd: 398.2556, Found: 398.2545 (M+H);

Analysis: Calcd: C, 66.47; H, 7.86; N, 17.62;

Found: C, 66.87; H, 7.62; N, 17.75;

NMR (CDCl₃, 300 MHz): 1.95-2.10 (m, 8H), 2.20 (s, 3H), 2.32 (s, 3H),2.44 (s, 3H), 3.38 (s, 3H), 3.42 (s, 3H), 3.50-3.70 (m, 4H), 4.58-4.70(m, 1H), 6.87 (d, J=8, 1H), 6.95 (s, 2H).

ak) CI-HRMS: Calcd: 338.1981, Found: 338.1971 (M+H);

Analysis: Calcd: C, 67.63; H, 6.87; N, 20.06;

Found: C, 67.67; H, 6.82; N, 20.31;

NMR (CDCl₃, 300 MHz): 2.15 (s, 3H), 2.29 (s, 3H), 2.35 (s, 3H), 2.43 (s,3H), 3.90 (t, J=8, 4H), 4.35-4.45 (m, 4H), 7.00-7.15 (m, 3H).

al) CI-HRMS: Calcd: 464.1297, Found: 464.1297 (M+H);

NMR (CDCl₃, 300 MHz): 2.28 (s, 3H), 2.40 (s, 3H), 3.40 (s, 6H), 3.75 (t,J=8, 4H), 3.83 (s, 3H), 4.20-4.50 (m, 4H), 6.93 (dd, J=8, 1, 1H), 7.20(s, 1H), 7.24 (d, J=1, 1H).

am) CI-HRMS: Calcd: 418.1242, Found: 418.1223 (M+H);

NMR (CDCl₃, 300 MHz): 1.00 (t, d, J=8, 1, 6H), 1.55-1.75 (m, 4H), 2.34(s, 3H), 2.49 (s, 3H), 2.84 (s, 3H), 4.15-4.27 (m, 1H), 6.19 (d, J=8,1H), 6.93 (dd, J=8, 1, 1H), 7.21-7.30 (m, 2H).

an) CI-HRMS: Calcd: 404.1086, Found: 404.1079(M+H);

NMR (CDCl₃, 300 MHz): 1.35 (t, J=8, 6H), 2.28 (s, 3H), 2.40 (s, 3H),3.83 (s, 3H), 3.90-4.08 (m, 2H), 4.08-4.20 (m, 2H), 6.92 (dd, J=8, 1,1H), 7.20-7.25 (m, 2H).

ao) CI-HRMS: Calcd: 308.1875, Found: 308.1872 (M+H);

NMR (CDCl₃, 300 MHz): 0.75-0.80 (m, 2H), 0.93-1.00 (m, 2H), 2.16 (s,3H), 2.28 (s, 3H), 2.35 (s, 3H), 2.53 (s, 3H), 3.00-3.10 (m, 1H),6.50-6.55 (m, 1H), 7.00-7.15 (m, 3H).

ap) CI-HRMS: Calcd: 397.1988, Found: 397.1984 (M+H);

NMR (CDCl₃, 300 MHz): 2.43 (s, 3H), 2.50 (s, 3H), 3.43 (s, 3H), 3.61(dd, J=8, 8, 2H), 3.69 (dd,J=8, 8, 2H), 3.88 (s, 3H), 4.58-4.70 (m, 1H),6.75 (d, J=8, 1H), 7.20 (dd, J=8, 1, 1H), 7.25 (d, J=1, 1H), 7.40 (s,1H).

aq) CI-HRMS: Calcd: 375.2297, Found: 375.2286 (M+H);

Analysis: Calcd: C, 70.56; H, 7.01; N, 22.44;

Found: C, 70.49; H, 6.99; N, 22.45;

NMR (CDCl₃, 300 MHz): 0.79-0.85 (m, 2H), 1.00-1.05 (m, 1H), 2.00 (s,6H), 2.19 (s, 3H), 2.32 (s, 3H), 2.44 (s, 3H), 2.84 (t, J=8, 2H),3.30-3.40 (m, 1H), 4.50 (t, J=8, 2H), 6.95 (s, 2H).

ar) CI-HRMS: Calcd: 434.1192, Found: 434.1189 (M+H);

Analysis: Calcd: C, 52.54; H, 5.58; N, 16.12; Br, 18.40; Found: C,52.75; H, 5.59; N, 16.09; Br, 18.67;

NMR (CDCl₃, 300 MHz): 2.19 (s, 3H), 2.30 (s, 3H), 2.47 (s, 3H), 3.43 (s,6H), 3.60 (dd, J=8, 8, 2H), 3.70 (dd, J=8,8, 2H), 4.58-4.70 (m, 1H),6.71 (d, J=8, 1H), 7.08 (d, J=8, 1H), 7.37 (dd, J=8, 1, 1H), 7.45 (d,J=1, 1H).

as) CI-HRMS: Calcd: 448.1348, Found: 448.1332 (M+H);

Analysis: Calcd: C, 53.58; H, 5.85; N, 16.62; Br, 17.82; Found: C,53.68; H, 5.74; N, 15.52; Br, 13.03;

NMR (CDCl₃, 300 MHz): 1.95-2.10 (m, 2H), 2.20 (s, 3H), 2.30 (s, 3H),2.47 (s, 3H), 3.38 (s, 3H), 3.41 (s, 3H), 3.50-3.67 (m, 4H), 4.55-4.70(m, 1H), 6.89 (d, J=8, 1H), 7.05 (d, J=8, 1H), 7.35 (dd, J=8, 1, 1H),7.47 (d, J=1, 1H).

at) CI-HRMS: Calcd: 400.2349, Found: 400.2348 (M+H);

Analysis: Calcd: C, C, 63.14; H, 7.32; N, 17.53;

Found: C,63.40; H, 7.08; N, 17.14;

NMR (CDCl₃, 300 MHz): 2.16 (s, 3H), 2.20 (s, 3H), 2.30 (s, 3H), 2.46 (s,3H), 3.42 (s, 6H), 3.60 (q, J=8, 2H), 3.70 (q, J=8, 2H), 3.85 (s, 3H),4.59-4.70 (m, 1H), 6.70 (d, J=8, 1H), 6.76 (s, 1H), 6.96 (s, 1H).

au) CI-HRMS: Calcd: 414.2505, Found: 414.2493 (M+H);

NMR (CDCl₃, 300 MHz): 2.15 (s, 3H), 2.19 (s, 3H), 2.25 (s, 3H), 2.40 (s,3H), 3.40 (s, 6H), 3.76 (t, J=8, 4H), 3.84 (s, 3H), 4.20-4.45 (m, 4H),6.77 (s, 1H), 6.93 (s, 1H).

av) CI-HRMS: Calcd: 368.2450, Found: 368.2447 (M+H);

NMR (CDCl₃, 300 MHz): 1.00 (t, J=8, 6H), 1.55-1.85 (m, 4H), 2.19 (s,3H), 2.20 (s, 3H), 2.30 (s, 3H), 2.47 (s, 3H), 3.88 (s, 3H), 4.10-4.30(m, 1H), 6.15 (d, J=8, 1H), 6.78 (s, 1H), 6.98 (s, 1H).

aw) CI-HRMS: Calcd: 353.2216, Found: 353.2197 (M+H);

NMR (CDCl₃, 300 MHz): 1.35 (t, J=8, 6H), 2.17 (s, 3H), 2.19 (s, 3H),2.28 (s, 3H), 2.40 (s, 3H), 3.85 (s, 3H), 3.90-4.20 (m, 4H), 6.78 (s,1H), 6.95 (s, 1H).

ax) CI-HRMS: Calcd: 390.1697, Found: 390.1688 (M+H);

Analysis: Calcd: C, 58.53; H, 6.20; N, 17.96; Cl, 9.09; Found: C, 58.95;H, 6.28; N, 17.73; Cl, 9.15;

NMR (CDCl₃, 300 MHz): 2.35 (s, 3H), 2.37 (s, 3H), 2.48 (s, 3H), 3.42 (s,6H), 3.60 (dd, J=8, 8, 2H) 3.68 (dd, J=8, 8, 2H), 4.59-4.72 (m, 1H),6.72 (d, J=8, 1H), 7.12 (d, J=8, 1H), 7.23 (d, J=8, 1H), 7.32 (s, 1H).

ay) CI-HRMS: Calcd: 374.1748, Found: 374.1735 (M+H);

Analysis: Calcd: C, 61.04; H, 6.47; N, 18.73; Cl, 9.48; Found: C, 61.47;H, 6.54; N, 18.23; Cl, 9.61;

NMR (CDCl₃, 300 MHz): 1.01 (t, J=8, 3H), 1.62-1.88 (m, 4H), 2.35 (s,3H), 2.37 (s, 3H), 2.48 (d, J=1, 3H), 3.40, 3.45 (s, s, 3H), 3.50-3.64(m, 2H), 4.38-4.47 (m, 1H), 6.53 (d, J=8, 1H), 7.12 (d, J=8, 1H), 7.07(d, J=8, 1H), 7.12 (s, 1H).

az) CI-HRMS: Calcd: 404.1853, Found: 404.1839 (M+H);

NMR (CDCl₃, 300 MHz): 2.29 (s, 3H), 2.38 (s, 3H), 2.40 (s, 3H), 3.40 (s,6H), 3.76 (t, J=8, 4H), 4.20-4.45 (m, 4H), 7.11 (d, J=8, 1H), 7.22 (d,J=8, 1H), 7.31 (s, 1H).

ba) CI-HRMS: Calcd: 404.1853, Found: 404.1859 (M+H);

Analysis: C, 59.47; H, 6.50; N, 17.34; Cl, 8.79;

Found: C, 59.73; H, 6.46; N, 17.10; Cl, 8.73;

NMR (CDCl₃, 300 MHz): 1.95-2.08 (m, 2H), 2.35 (s, 3H), 2.38 (s, 3H),2.46 (s, 3H), 3.38 (s, 3H), 3.41 (s, 3H), 3.50-3.65 (m, 4H), 4.56-4.70(m, 1H), 6.85 (d, J=8, 1H), 7.12 (d, J=8, 1H), 7.45 (d, J=8, 1H), 7.32(s, 1H).

bb) CI-HRMS: Calcd: 391.2246, Found: 391.2258 (M+H);

Analysis: C, 67.67; H, 6.71; N, 21.52; Found: C, 67.93; H, 6.70; N,21.48;

NMR (CDCl₃, 300 MHz): 0.76-0.84 (m, 2H), 0.84-0.91 (m, 2H), 1.00-1.08(m, 2H), 2.15 (s, 3H), 2.20 (s, 3H), 2.29 (s, 3H), 2.45 (s, 3H), 2.85(t, J=8, 2H), 3.28-3.30 (m, 1H), 3.85 (s, 3H), 6.78 (s, 1H), 6.95 (s,1H).

bc) CI-HRMS: Calcd: 386.2192, Found: 386.2181 (M+H);

Analysis: C, 62.32; H, 7.06; N, 18.17; Found: C, 62.48; H, 6.83; N,18.15;

NMR (CDCl₃, 300 MHz): 7.1 (d, 1H, J=8), 6.9 (d, 1H, J=1), 6.8 (dd, 1H,J=8,1), 6.7 (br.d, 1H, J=8), 4.7-4.6 (m, 1H), 3.85 (s, 3H), 3.70-3.55(m, 4H), 3.45 (s, 6H), 2.5 (s, 3H), 2.3 (s, 3H), 2.15 (s, 3H).

bd) CI-HRMS: Calcd: 400.2349, Found: 400.2336 (M+H);

NMR (CDCl₃, 300 MHz): 7.1 (d, 1H, J=7), 6.85 (d, 1H, J=1), 6.75 (dd, 1H,J=7,1), 4.45-4.25 (br.s, 4H), 3.75 (t, 4H, J 7), 3.4 (s, 6H), 2.4 (s,3H), 2.25 (s, 3H), 2.15 (s, 3H).

be) CI-HRMS: Calcd: 370.2243, Found: 370.2247 (M+H);

Analysis: C, 65.02; H, 7.38; N, 18.96; Found: C, 65.28; H, 7.27; N,18.71;

NMR (CDCl₃, 300 MHz): 7.1 (d, 1H, J=8), 6.85 (d, 1H, J=1), 6.8 (dd, 1H,J=8,1), 6.5 (br. d, 1H, J=1), 4.5-4.3 (m, 1H), 3.85 (s, 3H), 3.65-3.5(m, 2H), 3.4 (s, 2H), 2.5 (s, 3H), 2.3 (s, 3H), 2.2 (s, 3H), 1.9-1.7 (m,2H), 1.05 (t, 3H, J=7).

bf) CI-HRMS: Calcd: 379.2246, Found: 379.2248 (M+H);

NMR (CDCl₃, 300 MHz): 7.1 (d, 1H, J=8), 6.85 (d, 1H, J=1), 6.8 (dd, 1H,J=8,1), 4.3-4.0 (m, 4H), 3.85 (s, 3H), 3.0 (t, 2H, J=7), 2.45 (s, 3H),2.3 (s, 3H), 2.2 (s, 3H), 1.9-1.8 (m, 2H), 1.0 (t, 3H, J=7).

bg) CI-HRMS: Calcd: 340.2137, Found: 340.2122 (M+H);

NMR (CDCl₃, 300 MHz): 7.1 (d, 1H, J=8), 6.85 (d, 1H, J=1), 6.75 (dd, 1H,J=8,1), 4.2-4.0 (br.m, 4H), 3.85 (s, 3H, 2.4 (s, 3H), 2.3 (s, 3H), 2.2(s, 3H), 1.35 (t, 6H, J=7).

bh) CI-HRMS: Calcd: 313.1665, Found: 313.6664 (M+H).

bi) CI-HRMS: Calcd: 400.2349, Found: 400.2346 (M+H);

NMR (CDCl₃, 300 MHz): 7.1 (d, 1H, J=7), 6.9-6.75 (m, 3H), 4.7-4.55 (m,1H), 3.8 (s, 3H), 3,7-3.5 (m, 4H), 3.45 (s, 3H), 3.35 (s, 3H), 2.5 (s,3H), 2.3 (S, 3H), 2.2 (s, 3H), 2.1-1.95 (m, 2H).

bj) CI-HRMS: Calcd: 377.2090, Found: 377.2092 (M+H);

Analysis: C, 67.00; H, 6.44; N, 22.32; Found: C, 67.35; H, 6.44; N,22.23;

NMR (CDCl₃, 300 MHz): 7.1 (d, 1H, J=8), 6.9 (d, 1H, J=1), 6.8 (dd, 1H,J=8,1), 4.55-4.4 (m, 2H), 3.85 (s, 3H), 3.4-3.3 (m, 1H), 2.85 (t, 2H,J=7), 2.5 (s, 3H), 2.3 (s, 3H), 2.2 (s, 3H), 1.1-1.0 (m, 2H), 0.85-0.75(m, 2H).

bk) CI-HRMS: Calcd: 413.2427, Found: 413.2416 (M+H);

NMR (CDCl₃, 300Hz): 7.1 (d, 1H, J=8), 6.85 (d, 1H, J=1), 6.75 (dd, 1H,J=8,1), 4.6 (m, 1H), 3.85 (s, 3H), 3.75-3.6(m, 4H), 3.6 (q, 4H, J=7),2.5 (s, 3H), 2.3 s, 3H), 2.2 (s, 3H), 1.25 (t, 6H, J=7).

bl) CI-HRMS: Calcd: 420.1802, Found: 420.1825(M+H);

bm) CI-HRMS: Calcd: 390.1697, Found: 390.1707(M+H);

bn) CI-HRMS: Calcd: 397.1465, Found: 397.1462(M+H);

bo) CI-HRMS: Calcd: 360.1513, Found: 360.1514(M+H);

bp) CI-HRMS: Calcd: 374.1748, Found: 374.1737(M+H);

bq) CI-HRMS: Calcd: 479.1155, Found: 479.1154(M+H);

br) CI-HRMS: Calcd: 463.1219, Found: 463.1211(M+H);

Analysis Calcd: C, 51.96; H, 5.23; N, 15.15, Br, 17.28; Found: C, 52.29;H, 5.62; N, 14.79, Br, 17.47

bs) CI-HRMS: Calcd: 433.1113, Found: 433.1114(M, ⁷⁹Br);

bt) NH₃-CI MS: Calcd: 406, Found: 406 (M+H)+;

NMR (CDCl₃, 300 MHz): δ7.28 (d, J=10 Hz, 1H), 7.03 (d, J=8 Hz, 1H), 6.96(s, 1H), 6.7 (d, J=9, 1H), 4.63 (m, 1H), 3.79 (s, 3H), 3.6 (m, 4H), 3.42(s, 6H), 2.47 (s, 3H), 2.32 (s, 3H).

EXAMPLE 431 Preparation of2,4,7-dimethyl-8-(4-methoxy-2-methylphenyl)[1,5-a]-pyrazolo-1,3,5-triazine(Formula 1, where R³ is CH₃, R₁ is CH₃, Z is C—CH₃, Ar is2,4-dimethylphenyl)

5-Acetamidino-4-(4-methoxy-2-methylphenyl)-3-methylpyrazole, acetic acidsalt (602 mg, 2 mmol) was mixed with a saturated NaHCO₃ solution (10mL). The aqueous mixture was extracted with EtOAc three times. Thecombined organic layers were dried over MgSO₄, filtered and concentratedin vacuo. The residue was taken up in toluene (10 mL) and trimethylorthoacetate (0.36 g, 3 mmol) was added to the suspension. The reactionmixture was heated to reflux temperature under a nitrogen atmosphere andstirred for 16 hours. After being cooled to ambient temperature, thereaction mixture was concentrated in vacuo to give an oily solid. Columnchromatography (CHCl₃:MeOH::9:1) afforded, after removal of solvent invacuo, a yellow viscous oil (Rf=0.6, 210 mg, 37% yield): NMR (CDCl₃, 300MHz): 7.15 (d, 1H, J=8), 6.9 (d, 1H, J=1), 6.85 (dd, 1H, J=8,1), 3.85(s, 3H), 2.95 (s, 3H), 2.65 (s, 3H), 2.4 (s, 3H), 2.15 (s, 3H); CI-HRMS:Calcd: 283.1559, Found: 283.1554 (M+H).

EXAMPLE 4327-hydroxy-5-methyl-3-(2-chloro-4-methylphenyl)pyrazolo[1,5-a]pyrimidine(Formula 1 where A is CH, R1 is Me, R3 is OH, Z is C—Me, Ar is2-chloro-4-methylphenyl)

5-Amino-4-(2-chloro-4-methylphenyl)-3-methylpyrazole (1.86 g, 8.4 mmol)was dissolved in glacial acetic acid (30 mL) with stirring. Ethylacetoacetate (1.18 mL, 9.2 mmol) was then added dropwise to theresulting solution. The reaction mixture was then heated to refluxtemperature and stirred for 16 hours, then cooled to room temperature.Ether (100 mL) was added and the resulting precipitate was collected byfiltration. Drying in vacuo afforded a white solid (1.0 g, 42% yield):NMR (CDCl₃, 300Hz): 8.70 (br.s 1H), 7.29 (s, 1H), 7.21-7.09 (m, 2H),5.62 (s, 1H), 2.35 (s, 6H), 2.29 (s, 3H); CI-MS: 288 (M+H).

EXAMPLE 4337-chloro-5-methyl-3-(2-chloro-4-methylphenyl)pyrazolo[1,5-a]pyrimidine(Formula 1 where A is CH, R1 is Me, R3 is Cl, Z is C—Me, Ar is2-chloro-4-methylphenyl)

A mixture of7-hydroxy-5-methyl-3-(2-chloro-4-methylphenyl)-pyrazolo[1,5-a]pyrimidine(1.0 g, 3.5 mmol), phosphorus oxychloride (2.7 g, 1.64 mL, 17.4 mmol),N,N-diethylaniline (0.63 g, 0.7 mL, 4.2 mmol) and toluene (20 mL) wasstirred at reflux temperature for 3 hours, then it was cooled to ambienttemperature. The volatiles were removed in vacuo. Flash chromatography(EtOAc:hexane::1:2) on the residue gave7-chloro-5-methyl-3-(2-chloro-4-methylphenyl)-pyrazolo[1,5-a]pyrimidine(900 mg, 84% yield) as a yellow oil: NMR (CDCl₃, 300 Hz): 7.35 (s, 1H),7.28-7.26 (m, 1H), 71.6 (d, 1H, J=7), 6.80 (s, 1H), 2.55 (s, 3H), 2.45(s, 3H), 2.40 (s, 3H); CI-MS: 306 (M+H).

EXAMPLE 4347-(pentyl-3-amino)-5-methyl-3-(2-chloro-4-methylphenyl)pyrazolo[1,5-a]pyrimidine(Formula 1 where A is CH, R1 is Me, R3 is pentyl-3-amino, Z is C—Me, Aris 2-chloro-4-methylphenyl)

A solution of 3-pentylamine (394 mg, 6.5 mmol) and7-chloro-5-methyl-3-(2-chloro-4-methylphenyl)pyrazolo[1,5-a]pyrimidine(200 mg, 0.65 mmol) in dimethylsulfoxide (DMSO, 10 mL) was stirred at150° C. for 2 hours; then it was cooled to ambient temperature. Thereaction mixture was then poured onto water (100 mL) and mixed. Threeextractions with dichloromethane, washing the combined organic layerswith brine, drying over MgSO₄, filtration and removal of solvent invacuo produced a yellow solid. Flash chromatography (EtOAc:hexanes::1:4)afforded a white solid (140 mg, 60% yield): mp 139-141° C.; NMR (CDCl₃,300 Hz):7.32 (s, 1H), 7.27 (d, 1H, J=8), 7.12 (d, 1H, J=7), 6.02 (d, 1H,J=9), 5.78 (s, 1H), 3.50-3.39 (m, 1H), 2.45 (s, 3H), 2.36 (s, 6H),1.82-1.60 (m, 4H), 1.01 (t, 6H, J=8); Analysis Calcd for C₂OH₂₅ClN₄: C,67.31, H, 7.06; N, 15.70, Cl, 9.93; Found: C, 67.32; H, 6.95, N, 15.50;Cl, 9.93.

The examples delineated in TABLE 2 may be prepared by the methodsoutlined in Examples 1A, 1B, 432, 433, 434. Commonly used abbreviationsare: Ph is phenyl, Pr is propyl, Me is methyl, Et is ethyl, Bu is butyl,Ex is Example, EtOAc is ethyl acetate.

TABLE 2

mp Ex. Z R₃ Ar (° C.) 435^(b) C-Me N(CH₂CH₂OMe)₂ 2,4-Cl₂-Ph 71-73436^(c) C-Me N(Bu)Et 2,4-Cl₂-Ph 86-87 437^(d) C-Me NHCH(Et)CH₂OMe2,4-Cl₂-Ph 110- 111  438^(e) C-Me N(Pr)CH₂CH₂CN 2,4-Cl₂-Ph 83-85 439^(f)C-Me NH-3-pentyl 2,4-Cl₂-Ph 175- 176  440^(g) C-Me NHCH(CH₂OMe)₂2,4-Cl₂-Ph 107 441^(h) C-Me NHCH(Et)₂ 2,4-Me₂-Ph oil 442^(i) C-MeNHCH(CH₂OMe)₂ 2,4-Me₂-Ph 103- 105  443^(j) C-Me N(CH₂CH₂OMe)₂ 2,4-Me₂-Ph87-89 444^(k) C-Me N(c-Pr)CH₂CH₂CN 2,4-Me₂-Ph 133 (dec) 445^(l) C-MeN(CH₂CH₂OMe)₂ 2-Cl, 4-MePh 77-78 446^(m) C-Me NHCH(CH₂OMe)₂ 2-Cl, 4-MePh131- 133  447^(n) C-Me NHCH(Et)₂ 2-Cl, 4-MePh 139- 141  448^(o) C-MeNEt₂ 2,4-Me₂-Ph 92-94 449^(p) C-Me N(Pr)CH₂CH₂CN 2,4-Me₂-Ph 143- 144 450^(q) C-Me N(Bu)CH₂CH₂CN 2,4-Me₂-Ph 115- 117  451^(r) C-MeNHCH(Et)CH₂OMe 2,4-Me₂-Ph oil 452^(s) C-Me NHCH(Et)₂ 2-Me, 4- 104- MeOPh106  453^(t) C-Me NHCH(CH₂OMe)₂ 2-Me, 4- 115- MeOPh 116  454^(u) C-MeN(CH₂CH₂OMe)₂ 2-Me, 4- oil MeOPh 455^(v) C-Me (S)—NHCH(CH₂CH₂OMe)- 2-Me,4- oil (CH₂OMe) MeOPh 456^(w) C-Me (S)—NHCH(CH₂CH₂OMe)- 2,4-Me₂-Ph oil(CH₂OMe) 457^(x) C-Me N(CH₂CH₂OMe)₂ 2-Me, 4-ClPh oil 458^(y) C-Me NHEt2,4-Me₂-Ph oil 459^(z) C-Me NHCH(Et)₂ 2-Me, 4-ClPh 94-96 460^(aa) C-MeNHCH(CH₂OMe)₂ 2-Me, 4-ClPh 113- 114  461^(ab) C-Me N(Ac)Et 2,4-Me₂-Phoil 462^(ac) C-Me (S)—NHCH(CH₂CH₂OMe)- 2-Me, 4-ClPh oil (CH₂OMe)463^(ad) C-Me N(Pr)CH₂CH₂CN 2-Me, 4- 118- MeOPh 119  464^(ae) C-Me NEt₂2-Me, 4- 97-99 MeOPh 465^(af) C-Me (S)—NHCH(CH₂CH₂OMe)- 2-Cl, 4-MePh101- (CH₂OMe) 103  466^(ag) C-Me NEt₂ 2-Cl, 4-MePh 129- 130  467^(ah)C-Me N(c-Pr)CH₂CH₂CN 2-Me, 4- 177- MeOPh 178  468^(ai) C-MeN(c-Pr)CH₂CH₂CN 2-Cl, 4-MePh 162- 163  469^(aj) C-Me NHCH(Et)CH₂OMe2-Me, 4- oil MeOPh 470^(ak) C-Me NHCH(Et)CH₂OMe 2-Cl, 4-MePh 111- 113 471 C-Me NHCH(CH₂OMe)₂ 2-Cl-4-MeOPh 472 C-Me N(CH₂CH₂OMe)₂ 2-Cl-4-MeOPh473 C-Me NHCH(Et)CH₂OMe 2-Cl-4-MeOPh 474 C-Me N(c-Pr)CH₂CH₂CN2-Cl-4-MeOPh 475 C-Me NEt₂ 2-Cl-4-MeOPh 476 C-Me NH-3-pentyl2-Cl-4-MeOPh 477 C-Me NHCH(Et)CH₂CH₂OMe 2-Cl-4-MeOPh 478 C-MeNHCH(Me)CH₂CH₂OMe 2-Cl-4-MeOPh 479 C-Me NHCH(Et)CH₂CH₂OMe 2-Br-4-MeOPh480 C-Me NHCH(Me)CH₂CH₂OMe 2-Br-4-MeOPh 481 C-Me NHCH(Et)CH₂CH₂OMe2-Me-4- MeOPh 482 C-Me NHCH(Me)CH₂CH₂OMe 2-Me-4- MeOPh 483 C-MeNHCH(CH₂OMe)₂ 2-Cl-4,5- (MeO)₂Ph 484 C-Me N(CH₂CH₂OMe)₂ 2-Cl-4,5-(MeO)₂Ph 485 C-Me NHCH(Et)CH₂OMe 2-Cl-4,5- (MeO)₂Ph 486 C-MeN(c-Pr)CH₂CH₂CN 2-Cl-4,5- (MeO)₂Ph 487 C-Me NEt₂ 2-Cl-4,5-  99- (MeO)₂Ph101  488 C-Me NH-3-pentyl 2-Cl-4,5- 169- (MeO)₂Ph 170 489 C-MeNHCH(Et)CH₂CH₂OMe 2-Cl-4,5- (MeO)₂Ph 490 C-Me NHCH(Me)CH₂CH₂OMe2-Cl-4,5- (MeO)₂Ph 491 C-Me NHCH(CH₂OMe)₂ 2-Br-4,5- 90-93 (MeO)₂Ph 492C-Me N(CH₂CH₂OMe)₂ 2-Br-4,5- 110 (MeO)₂Ph 493 C-Me NHCH(Et)CH₂OMe2-Br-4,5- (MeO)₂Ph 494 C-Me N(c-Pr)CH₂CH₂CN 2-Br-4,5- (MeO)₂Ph 495 C-MeNEt₂ 2-Br-4,5- (MeO)₂Ph 496 C-Me NH-3-pentyl 2-Br-4,5- (MeO)₂Ph 497 C-MeNHCH(Et)CH₂CH₂OMe 2-Br-4,5- (MeO)₂Ph 498 C-Me NHCH(Me)CH₂CH₂OMe2-Br-4,5- (MeO)₂Ph 499 C-Me NHCH(CH₂OMe)₂ 2-Cl-4,6- (MeO)₂Ph 500 C-MeN(CH₂CH₂OMe)₂ 2-Cl-4,6- (MeO)₂Ph 501 C-Me NHCH(Et)CH₂OMe 2-Cl-4,6-(MeO)₂Ph 502 C-Me N(c-Pr)CH₂CH₂CN 2-Cl-4,6- (MeO)₂Ph 503 C-Me NEt₂2-Cl-4,6- (MeO)₂Ph 504 C-Me NH-3-pentyl 2-Cl-4,6- (MeO)₂Ph 505 C-MeNHCH(Et)CH₂CH₂OMe 2-Cl-4,6- (MeO)₂Ph 506 C-Me NHCH(Me)CH₂CH₂OMe2-Cl-4,6- (MeO)₂Ph 507 C-Me NHCH(CH₂OMe)₂ 2-Me-4,6- (MeO)₂Ph 508 C-MeN(CH₂CH₂OMe)₂ 2-Me-4,6- (MeO)₂Ph 509 C-Me NHCH(Et)CH₂OMe 2-Me-4,6-(MeO)₂Ph 510 C-Me N(c-Pr)CH₂CH₂CN 2-Me-4,6- (MeO)₂Ph 511 C-Me NEt₂2-Me-4,6- (MeO)₂Ph 512 C-Me NH-3-pentyl 2-Me-4,6- (MeO)₂Ph 513 C-MeNHCH(Et)CH₂CH₂OMe 2-Me-4,6- (MeO)₂Ph 514 C-Me NHCH(Me)CH₂CH₂OMe2-Me-4,6- (MeO)₂Ph 515 C-Me N(c-Pr)CH₂CH₂CN 2-Br-4,6- (MeO)₂Ph 516 C-MeNEt₂ 2-Br-4,6- (MeO)₂Ph 517 C-Me NH-3-pentyl 2-Br-4,6- (MeO)₂Ph 518 C-MeNHCH(Et)CH₂CH₂OMe 2-Br-4,6- (MeO)₂Ph 519 C-Me NHCH(Me)CH₂CH₂OMe2-Br-4,6- (MeO)₂Ph 520 C-Me NHCH(Et)CH₂CH₂OMe 2-Me-4- MeOPh 521 C-MeNHCH(Me)CH₂CH₂OMe 2-Me-4- MeOPh 522 C-Me NHCH(CH₂OMe)₂ 2-MeO-4- MePh 523C-Me N(CH₂CH₂OMe)₂ 2-MeO-4- MePh 524 C-Me NHCH(Et)CH₂OMe 2-MeO-4- MePh525 C-Me N(c-Pr)CH₂CH₂CN 2-MeO-4- MePh 526 C-Me NEt₂ 2-MeO-4- MePh 527C-Me NH-3-pentyl 2-MeO-4- MePh 528 C-Me NHCH(Et)CH₂CH₂OMe 2-MeO-4- MePh529 C-Me NHCH(Me)CH₂CH₂OMe 2-MeO-4- MePh 530 C-Me NHCH(CH₂OMe)₂ 2-MeO-4-MePh 531 C-Me N(CH₂CH₂OMe)₂ 2-MeO-4- MePh 532 C-Me NHCH(Et)CH₂OMe2-MeO-4- MePh 533 C-Me N(c-Pr)CH₂CH₂CN 2-MeO-4- MePh 534 C-Me NEt₂2-MeO-4- MePh 535 C-Me NH-3-pentyl 2-MeO-4- MePh 536 C-MeNHCH(Et)CH₂CH₂OMe 2-MeO-4- MePh 537 C-Me NHCH(Me)CH₂CH₂OMe 2-MeO-4- MePh538 C-Me NHCH(CH₂OMe)₂ 2-MeO-4-ClPh 539 C-Me N(CH₂CH₂OMe)₂ 2-MeO-4-ClPh540 C-Me NHCH(Et)CH₂OMe 2-MeO-4-ClPh 541 C-Me N(C-Pr)CH₂CH₂CN2-MeO-4-ClPh 542 C-Me NEt₂ 2-MeO-4-ClPh 543 C-Me NH-3-pentyl2-MeO-4-ClPh 544 C-Me NHCH(Et)CH₂CH₂OMe 2-MeO-4-ClPh 545 C-MeNHCH(Me)CH₂CH₂OMe 2 MeO 4-ClPh

Notes for Table 2

b) CI-HRMS: Calcd: 423.1355; Found: 423.1337 (M+H).

c) Analysis: Calcd: C, 61.38; H, 6.18; N, 14.32; Found: C, 61.54; H,6.12; N, 14.37.

d) Analysis: Calcd: C, 58.02; H, 5.65; N, 14.24; Found: C, 58.11; H,5.52; N, 14.26.

e) Analysis: Calcd: C, 59.71; H, 5.26; N, 14.85; Found: C, 59.94; H,5.09; N, 17.23.

f) Analysis: Calcd: C, 60.48; H, 5.89; N, 14.85; Found: C, 60.62; H,5.88; N, 14.82.

h) CI-HRMS: Calcd: 337.2388; Found: 337.2392 (M+H).

i) Analysis: Calcd: C, 68.45; H, 7.669; N, 15.21; Found: C, 68.35; H,7.49; N, 14.91.

j) Analysis: Calcd: C, 69.08; H, 7.915; N, 14.65; Found: C, 68.85; H,7.83; N, 14.54.

k) Analysis: Calcd: C, 73.51; H, 7.01; N, 19.48; Found: C, 71.57; H,7.15; N, 19.12.

l) CI-HRMS: Calcd: 403.1899; Found: 403.1901 (M+H).

m) Analysis: Calcd: C, 61.77; H, 6.49; N, 14.41; Cl. 9.13; Found: C,61.90; H, 6.66; N, 13.62; Cl, 9.25.

n) Analysis: Calcd: C, 67.31; H, 7.06; N, 15.70; Cl. 9.93; Found: C,67.32; H, 6.95; N, 15.50; Cl, 9.93.

o) Analysis: Calcd: C, 74.50; H, 8.14; N, 17.38; Found: C, 74.43; H,7.59; N, 17.16.

p) Analysis: Calcd: C, 73.10; H, 7.54; N, 19.37; Found: C, 73.18; H,7.59; N, 18.81.

q) Analysis: Calcd: C, 73.57; H, 7.78; N, 18.65; Found: C, 73.55; H,7.79; N, 18.64.

r) CI-HRMS: Calcd: 353.2333; Found: 353.2341 (M+H).

s) Analysis: Calcd: C, 71.56; H, 8.02; N, 15.90; Found: C, 71.45; H,7.99; N, 15.88.

t) Analysis: Calcd: C, 65.60; H, 7.34; N, 14.57; Found: C, 65.42; H,7.24; N, 14.37.

u) CI-HRMS: Calcd: 399.2398; Found: 399.2396 (M+H).

v) CI-HRMS: Calcd: 399.2398; Found: 399.2396 (M+H).

w) CI-HRMS: Calcd: 383.2450; Found: 383.2447 (M+H).

x) CI-HRMS: Calcd: 403.1887; Found: 403.1901 (M+H).

y) CI-HRMS: Calcd: 295.1919; Found: 295.1923 (M+H).

z) Analysis: Calcd: C, 67.31; H, 7.06; N, 15.70; Found: C, 67.12; H,6.86; N, 15.53.

aa) Analysis: Calcd: C, 61.77; H, 6.49; N, 14.41; Cl, 9.13; Found: C,62.06; H, 6.37; N, 14.25; Cl, 9.12.

ab) CI-HRMS: Calcd: 337.2017; Found: 337.2028 (M+H).

ac) CI-HRMS: Calcd: 403.1893; Found: 403.1901 (M+H).

ad) Analysis: Calcd: C, 70.00; H, 7.22; N, 18.55; Found: C, 70.05; H,7.22; N, 18.36.

ae) Analysis: Calcd: C, 70.98; H, 7.74; N, 16.55; Found: C, 71.15;H,7.46; N, 16.56.

ag) Analysis: Calcd: C, 66.59; H, 6.76; N, 16.34; Found: C, 66.69;H,6.82; N, 16.20.

ah) Analysis: Calcd: C, 70.38; H, 6.71; N, 18.65; Found: C, 70.35;H,6.82; N, 18.83.

ai) Analysis: Calcd: C, 66.39; H, 5.85; N, 18.44; Cl, 9.33; Found: C,66.29; H, 5.51; N, 18.36; Cl, 9.31.

aj) CI-HRMS: Calcd: 369.2278; Found: 369.2291 (M+H).

ak) Analysis: Calcd: C, 64.42; H, 6.77; N, 15.02; Found: C, 64.59;H,6.51, N, 14.81.

The examples delineated in TABLE 3 may be prepared by the methodsoutlined in Examples 1, 2, 3 or 6. Commonly used abbreviations are: Phis phenyl, Pr is propyl, Me is methyl, Et is ethyl, Bu is butyl, Ex isExample.

TABLE 3

mp Ex. Z R₃ Ar (° C.) 546^(a) C-Me NHCH(Et)₂ 2-Me-4- 164- Me₂N-Ph 166 547^(b) C-Me S—NHCH(CH₂CH₂OMe)- 2,4-Me₂-Ph oil CH₂OMe 548^(c) C-MeS—NHCH(CH₂CH₂OMe)- 2-Me-4- oil CH₂OMe Cl-Ph 549^(d) C-Me N(c-Pr)CH₂CH₂CN2-Me-4- 115- Cl-Ph 116  550^(e) C-Me NHCH(Et)CH₂CN 2-Me-4- 131- Cl-Ph132  551^(f) C-Me N(Et)₂ 2,3-Me₂-4- oil OMe-Ph 552^(g) C-MeN(CH₂CH₂OMe)CH₂CH₂OH 2,4-Cl₂-Ph oil 553^(h) C-Me N(CH₂CH₂OMe)₂ 2,3-Me₂-oil 4-OMe-Ph 554^(i) C-Me NHCH(Et)₂ 2,3-Me₂- 123- 4-OMePh 124  555^(j)C-Me N(CH₂-c-Pr)Pr 2-Me-4- oil Cl-Ph 556^(k) C-Me N(c-Pr)CH₂CH₂CN2,3-Me₂- 158- 4-OMePh 160  557 C-Me N(c-Pr)Et 2-Cl-4- OMePh 558 C-MeN(c-Pr)Me 2-Cl-4- OMePh 559 C-Me N(c-Pr)Pr 2-Cl-4- OMePh 560 C-MeN(c-Pr)Bu 2-Cl-4- OMePh 561^(l) C-Me N(Et)₂ 2-Cl-4- 115- CN-Ph 117  562C-Me N(c-Pr)₂ 2-Cl-4-OMe 127- 129  563^(m) C-Me NHCH(CH₂OH)₂ 2,4-Cl₂-Ph128- 129  564 C-Me N(c-Pr)Et 2-Br-4,5- (MeO)2Ph 565 C-Me N(c-Pr)Me 2Br-4,5- (MeO)2Ph 566 C-Me NH-c-Pr 2-Me-4- 126- MeOPh 128  567 C-MeNHCH(Et)CH2OH 2-Me-4- 60- MeOPh 62  568 C-Me NMe₂ 2-Br-4,5- (MeO)2Ph 569C-Me NHCH(Et)₂ 2-Me-4- 103- MeOPh 105  570 C-Me N(c-Pr)Et 2-Me-4- 173-MeOPh 174  571 C-Me NH-2-pentyl 2,4-Cl₂-Ph 118- 120  572 C-MeNHCH(Et)CH2CN 2,4-Cl₂-Ph 141- 142  573 C-Me NHCH(Pr)CH2OMe 2,4-Cl₂-Ph87- 88  574 C-Me NHCH(CH2-iPr)CH2OMe 2,4-Cl₂-Ph a- mor- phous 575 C-MeNH-2-butyl 2,4-Me₂-Ph oil 576 C-Me NH-2-pentyl 2,4-Me₂-Ph oil 577 C-MeNH 2-hexyl 2,4-Me₂-Ph oil 578 C-Me NHCH(i-Pr)Me 2,4-Me₂-Ph oil 579 C-MeNHCH(Me)CH₂-iPr 2,4-Me₂-Ph oil 580 C-Me NHCH(Me)-c-C6H11 2,4-Me₂-Ph oil581 C-Me NH-2-indanyl 2,4-Me₂-Ph oil 582 C-Me NH-1-indanyl 2,4-Me₂-Phoil 583 C-Me NHCH(Me)Ph 2,4-Me₂-Ph oil 584 C-Me NHCH(Me)CH₂-(4-ClPh)2,4-Me₂-Ph oil 585 C-Me NHCH(Me)CH₂COCH₃ 2,4-Me₂-Ph oil 586 C-MeNHCH(Ph)CH₂Ph 2,4-Me₂-Ph oil 587 C-Me NHCH(Me)(CH₂)3NEt₂ 2,4-Me₂-Ph oil588 C-Me NH-(2-Ph-c-C₃H₄) 2,4-Me₂-Ph oil 589 C-Me NHCH(Et)CH₂CN2,4-Me₂-Ph 119- 120  590 C-Me NH-3-hexyl 2,4-Me₂-Ph oil 591^(n) C-MeNEt₂ 2-MeO-4- oil ClPh 592^(o) C-Me NHCH(Et)₂ 2-MeO-4- oil ClPh 593^(p)C-Me NHCH(Et)CH₂OMe 2-MeO-4- oil ClPh 594 C-Me NMe₂ 2-MeO-4- oil ClPh595^(q) C-Me NHCH(Et)₂ 2-OMe- oil 4-MePh 596^(r) C-Me NEt₂ 2-OMe- oil4-MePh 597^(s) C-c- NHCH(CH₂OMe)₂ 2,4-Cl₂-Ph oil Pr 598 C-Me N(c-Pr)Et2,4-Me₂-Ph 599 C-Me N(c-Pr)Et 2,4-Cl₂-Ph 600 C-Me N(c-Pr)Et 2,4,6-Me₃-Ph 601 C-Me N(c-Pr)Et 2-Me-4- Cl-Ph 602 C-Me N(c-Pr)Et 2-Cl-4- Me-Ph603 C-Me NHCH(c-Pr)₂ 2,4-Cl₂-Ph 604 C-Me NHCH(c-Pr)₂ 2,4-Me₂-Ph 605 C-MeNHCH(c-Pr)₂ 2-Me-4- Cl-Ph 606 C-Me NHCH(c-Pr)₂ 2-Cl-4- Me-Ph 607 C-MeNHCH(c-Pr)₂ 2-Me-4- OMe-Ph 608 C-Me NHCH(c-Pr)₂ 2-Cl-4- OMe-Ph 609 C-MeNHCH(CH₂OMe)₂ 2-Cl-5- F-OMePh 610 C-Me NEt₂ 2-Cl-5- F-OMePh 611 C-MeN(c-Pr)CH₂CH₂CN 2-Cl-5- F-OMePh 612 C-Me NHCH(Et)₂ 2-Cl-5- F-OMePh 613C-Me N(CH₂CH₂OMe)₂ 2-Cl-5- F-OMePh 614 C-Me NEt₂ 2,6-Me₂- pyrid-3-yl 615C-Me N(c-Pr)CH₂CH₂CN 2,6-Me₂- pyrid-3-yl 616 C-Me NHCH(Et)₂ 2,6-Me₂-pyrid-3-yl 617 C-Me N(CH₂CH₂OMe)₂ 2,6-Me₂- pyrid-3-yl 618 C—OHNHCH(CH₂OMe)₂ 2,4-Me₂-Ph 619 C—OH NEt₂ 2,4-Me₂-Ph 620 C—OHN(c-Pr)CH₂CH₂CN 2,4-Me₂-Ph 621 C—OH NHCH(Et)₂ 2,4-Me₂-Ph 623 C—OHN(CH₂CH₂OMe)₂ 2,4-Me₂-Ph 624 C—NEt₂ NHCH(CH₂OMe)₂ 2,4-Me₂-Ph 625 C—NEt₂NEt₂ 2,4-Me₂-Ph 626 C—NEt₂ N(c-Pr)CH₂CH₂CN 2,4-Me₂-Ph 627 C—NEt₂NHCH(Et)₂ 2,4-Me₂-Ph 628 C—NEt₂ N(CH₂CH₂OMe)₂ 2,4-Me₂-Ph 629 C-MeNHCH(Et)₂ 2-Me-4- CN-Ph 630 C-Me N(CH₂CH₂OMe)₂ 2-Me-4- CN-Ph

Notes for Table 3

a) CI-HRMS: Calcd:367.2610, Found: 367.2607 (M+H).

b) CI-HRMS: Calcd:384.2400, Found: 384.2393 (M+H).

c) CI-HRMS: Calcd:404.1853, Found: 404.1844 (M+H).

d) CI-HRMS: Calcd:381.1594, Found: 381.1596 (M+H). Analysis: Calcd: C,63.07; H, 5.57; N, 22.07; Cl, 9.32; Found: C, 63.40; H, 5.55; N, 21.96;Cl, 9.15.

e) CI-HRMS: Calcd:369.1594, Found: 369.1576 (M+H).

f) CI-HRMS: Calcd:354.2216, Found: 354.2211 (M+H).

g) CI-HRMS: Calcd:410.1072, Found: 410.1075 (M+H).

h) CI-HRMS: Calcd:414.2427, Found: 414.2427(M+H).

i) CI-HRMS: Calcd:368.2372, Found: 368.2372(M+H).

j) CI-HRMS: Calcd:384.1955, Found: 384.1947(M+H).

k) CI-HRMS: Calcd:391.2168, Found: 391.2160(M+H).

l) CI-HRMS: Calcd:335.1984, Found: 335.1961(M+H).

m) CI-HRMS: Calcd:382.0759, Found: 382.0765(M+H).

n) NH₃-CI MS: Calcd: 360, Found: 360 (M+H)+.

o) NH₃-CI MS: Calcd: 374, Found: 374 (M+H)+. NMR (CDCl₃, 300 MHz): δ7.29(d, J=8.4 Hz, 1H), 7.04 (dd, J=1.8, 8 Hz, 1H), 6.96 (d, J=1.8 Hz, 1H),6.15 (d, J=10, 1 H), 4.19 (m, 1H), 3.81 (s, 3H), 2.47 (s, 3H), 2.32 (s,3H), 1.65 (m, 4H), 0.99 (t, J=7.32 Hz, 6H).

p) NH₃-CI MS: Calcd: 390; Found: 390 (M+H)+; NMR (CDCl₃, 300 MHz): δ7.28(d, J=8 Hz, 1H), 7.03 (d, J=8 Hz, 1H), 6.96 (s, 1H), 6.52 (d, J=9 Hz,1H), 4.36 (m, 1H), 3.8 (s, 3H), 3.55 (m, 2H), 3.39 (s, 3H), 2.47 (s,3H), 2.32 (s, 3H), 1.76 (m, 2H), 1.01 (t, J=7.32 Hz, 3H).

q) CI-HRMS: Calcd: 354.2294; Found: 354.2279 (M+H)+.

r) CI-HRMS: Calcd: 340.2137; Found: 340.2138 (M+H)+.

s) CI-HRMS: Calcd: 436.1307; Found: 436.1296 (M+H)+.

The examples delineated in TABLE 4 may be prepared by the methodsoutlined in Examples 1A, 1B, 432, 433, 434. Commonly used abbreviationsare: Ph is phenyl, Pr is propyl, Me is methyl, Et is ethyl, Bu is butyl,Ex is Example, EtOAc is ethyl acetate.

TABLE 4

Ex. Z R₃ Ar mp (° C.) 631 C-Me NHCH(Et)₂ 2-Br-4,5-(MeO)₂Ph 160-161 632C-Me NHCH(Et)₂ 2-Br-4-MeOPh 110-111 633 C-Me N(CH₂CH₂OMe)₂ 2-Br-4-MeOPh74-76 634 C-Me NHCH(CH₂OMe)₂ 2-Br-4-MeOPh 128-130 635 C-Me N(Et)₂2-Me-4-ClPh 113-114 636 C-Me N(c-Pr)Et 2,4-Cl₂Ph 637 C-Me N(c-Pr)Et2,4-Me₂Ph 638 C-Me N(c-Pr)Et 2,4,6-Me₃Ph 639 C-Me N(c-Pr)Et 2-Me-4-MeOPh640 C-Me N(c-Pr)Et 2-Cl-4-MeOPh 641 C-Me N(c-Pr)Et 2-Cl-4-MePh 642 C-MeN(c-Pr)Et 2-Me-4-ClPh 643 C-Me NHCH(c-Pr)₂ 2,4-Cl₂-Ph 644 C-MeNHCH(c-Pr)₂ 2,4-Me₂-Ph 645 C-Me NHCH(c-Pr)₂ 2-Me-4-Cl-Ph 646 C-MeNHCH(c-Pr)₂ 2-Cl-4-Me-Ph 647 C-Me NHCH(c-Pr)₂ 2-Me-4-OMe-Ph 648 C-MeNHCH(c-Pr)₂ 2-Cl-4-OMe-Ph 649 C-Me NHCH(CH₂OMe)₂ 2-Cl-5-F-OMePh 650 C-MeNEt₂ 2-Cl-5-F-OMePh 651 C-Me N(c-Pr)CH₂CH₂CN 2-Cl-5-F-OMePh 652 C-MeNHCH(Et)₂ 2-Cl-5-F-OMePh 653 C-Me N(CH₂CH₂OMe)₂ 2-Cl-5-F-OMePh 654 C-MeNEt₂ 2,6-Me₂-pyrid-3-yl 655 C-Me N(c-Pr)CH₂CH₂CN 2,6-Me₂-pyrid-3-yl 656C-Me NHCH(Et)₂ 2,6-Me₂-pyrid-3-yl 657 C-Me N(CH₂CH₂OMe)₂2,6-Me₂-pyrid-3-yl 658 C—OH NHCH(CH₂OMe)₂ 2,4-Me₂-Ph 659 C—OH NEt₂2,4-Me₂-Ph 660 C—OH N(c-Pr)CH₂CH₂CN 2,4-Me₂-Ph 661 C—OH NHCH(Et)₂2,4-Me₂-Ph 662 C—OH N(CH₂CH₂OMe)₂ 2,4-Me₂-Ph 663 C—NEt₂ NHCH(CH₂OMe)₂2,4-Me₂-Ph 664 C—NEt₂ NEt₂ 2,4-Me₂-Ph 665 C—NEt₂ N(c-Pr)CH₂CH₂CN2,4-Me₂-Ph 666 C—NEt₂ NHCH(Et)₂ 2,4-Me₂-Ph 667 C—NEt₂ N(CH₂CH₂OMe)₂2,4-Me₂-Ph 668 C-Me NHCH(Et)₂ 2-Me-4-CN-Ph 669 C-Me N(CH₂CH₂OMe)₂2-Me-4-CN-Ph

The examples in Tables 5 or 6 may be prepared by the methods illustratedin Examples 1A, 1B, 2, 3, 6, 431, 432, 433, 434 or by appropriatecombinations thereof. Commonly used abbreviations are: Ph is phenyl, Pris propyl, Me is methyl, Et is ethyl, Bu is butyl, Ex is Example.

TABLE 5

Ex. R₁₄ R₃ Ar 670 Me NHCH(CH₂OMe)₂ 2,4-Cl₂-Ph 671 Me NHCHPr₂ 2,4-Cl₂-Ph672 Me NEtBu 2,4-Cl₂-Ph 673 Me NPr(CH₂-c-C₃H₅) 2,4-Cl₂-Ph 674 MeN(CH₂CH₂OMe)₂ 2,4-Cl₂-Ph 675 Me NH-3-heptyl 2,4-Cl₂-Ph 676 MeNHCH(Et)CH₂OMe 2,4-Cl₂-Ph 677 Me NEt₂ 2,4-Cl₂-Ph 678 Me NHCH(CH₂OEt)₂2,4-Cl₂-Ph 679 Me NH-3-pentyl 2,4-Cl₂-Ph 680 Me NMePh 2,4-Cl₂-Ph 681 MeNPr₂ 2,4-Cl₂-Ph 682 Me NH-3-hexyl 2,4 Cl₂-Ph 683 Me morpholino2,4-Cl₂-Ph 684 Me N(CH₂Ph)CH₂CH₂OMe 2,4-Cl₂-Ph 685 Me NHCH(CH₂Ph)CH₂OMe2,4-Cl₂-Ph 686 Me NH-4-tetrahydropyranyl 2,4-Cl₂-Ph 687 MeNH-cyclopentyl 2,4-Cl₂-Ph 688 Me OEt 2,4-Cl₂-Ph 689 Me OCH(Et)CH₂OMe2,4-Cl₂-Ph 690 Me OCH₂Ph 2,4-Cl₂-Ph 691 Me O-3-pentyl 2,4-Cl₂-Ph 692 MeSEt 2,4-Cl₂-Ph 693 Me S(O)Et 2,4-Cl₂-Ph 694 Me SO₂Et 2,4-Cl₂-Ph 695 MePh 2,4-Cl₂-Ph 696 Me 2-CF₃-Ph 2,4-Cl₂-Ph 697 Me 2-Ph-Ph 2,4-Cl₂-Ph 698Me 3-pentyl 2,4-Cl₂-Ph 699 Me cyclobutyl 2,4-Cl₂-Ph 700 Me 3-pyridyl2,4-Cl₂-Ph 701 Me CH(Et)CH₂CONMe₂ 2,4-Cl₂-Ph 702 Me CH(Et)CH₂CH₂NMe₂2,4-Cl₂-Ph 703 Me NHCH(CH₂OMe)₂ 2,4,6-Me₃-Ph 704 Me NHCHPr₂ 2,4,6-Me₃-Ph705 Me NEtBu 2,4,6-Me₃-Ph 706 Me NPr(CH₂-c-C₃H₅) 2,4,6-Me₃-Ph 707 MeN(CH₂CH₂OMe)₂ 2,4,6-Me₃-Ph 708 Me NH-3-heptyl 2,4,6-Me₃-Ph 709 MeNHCH(Et)CH₂OMe 2,4,6-Me₃-Ph 710 Me NEt₂ 2,4,6-Me₃-Ph 711 MeNHCH(CH₂OEt)₂ 2,4,6-Me₃-Ph 712 Me NH-3-pentyl 2,4,6-Me₃-Ph 713 Me NMePh2,4,6-Me₃-Ph 714 Me NPr₂ 2,4,6-Me₃-Ph 715 Me NH-3-hexyl 2,4,6-Me₃-Ph 716Me morpholino 2,4,6-Me₃-Ph 717 Me N(CH₂Ph)CH₂CH₂OMe 2,4,6-Me₃-Ph 718 MeNHCH(CH₂Ph)CH₂OMe 2,4,6-Me₃-Ph 719 Me NH-4-tetrahydropyranyl2,4,6-Me₃-Ph 720 Me NH-cyclopentyl 2,4,6-Me₃-Ph 721 Me OEt 2,4,6-Me₃-Ph722 Me OCH(Et)CH₂OMe 2,4,6-Me₃-Ph 723 Me OCH₂Ph 2,4,6-Me₃-Ph 724 MeO-3-pentyl 2,4,6-Me₃-Ph 725 Me SEt 2,4,6-Me₃-Ph 726 Me S(O)Et2,4,6-Me₃-Ph 727 Me SO₂Et 2,4,6-Me₃-Ph 728 Me CH(CO₂Et)₂ 2,4,6-Me₃-Ph729 Me C(Et)(CO₂Et)₂ 2,4,6-Me₃-Ph 730 Me CH(Et)CH₂OH 2,4,6-Me₃-Ph 731 MeCH(Et)CH₂OMe 2,4,6-Me₃-Ph 732 Me CONMe₂ 2,4,6-Me₃-Ph 733 Me COCH₃2,4,6-Me₃-Ph 734 Me CH(OH)CH₃ 2,4,6-Me₃-Ph 735 Me C(OH)Ph-3-pyridyl2,4,6-Me₃-Ph 736 Me Ph 2,4,6-Me₃-Ph 737 Me 2-Ph-Ph 2,4,6-Me₃-Ph 738 Me3-pentyl 2,4,6-Me₃-Ph 739 Me cyclobutyl 2,4,6-Me₃-Ph 740 Me 3-pyridyl2,4,6-Me₃-Ph 741 Me CH(Et)CH₂CONMe₂ 2,4,6-Me₃-Ph 742 Me CH(Et)CH₂CH₂NMe₂2,4,6-Me₃-Ph 743 Me NHCH(CH₂OMe)₂ 2,4-Me₂-Ph 744 Me N(CH₂CH₂OMe)₂2,4-Me₂-Ph 745 Me NHCH(Et)CH₂OMe 2,4-Me₂-Ph 746 Me NH-3-pentyl2,4-Me₂-Ph 747 Me NEt₂ 2,4-Me₂-Ph 748 Me N(CH₂CN)₂ 2,4-Me₂-Ph 749 MeNHCH(Me)CH₂OMe 2,4-Me₂-Ph 750 Me OCH(Et)CH₂OMe 2,4-Me₂-Ph 751 MeNPr-c-C₃H₅ 2,4-Me₂-Ph 752 Me NHCH(Me)CH₂NMe₂ 2,4-Me₂-Ph 753 MeN(c-C₃H₅)CH₂CH₂CN 2,4-Me₂-Ph 754 Me N(Pr)CH₂CH₂CN 2,4-Me₂-Ph 755 MeN(Bu)CH₂CH₂CN 2,4-Me₂-Ph 756 Me NHCHPr₂ 2,4-Me₂-Ph 757 Me NEtBu2,4-Me₂-Ph 758 Me NPr(CH₂-c-C₃H₅) 2,4-Me₂-Ph 759 Me NH-3-heptyl2,4-Me₂-Ph 760 Me NEt₂ 2,4-Me₂-Ph 761 Me NHCH(CH₂OEt)₂ 2,4-Me₂-Ph 762 MeNH-3-pentyl 2,4-Me₂-Ph 763 Me NMePh 2,4-Me₂-Ph 764 Me NPr₂ 2,4-Me₂-Ph765 Me NH-3-hexyl 2,4-Me₂-Ph 766 Me morpholino 2,4-Me₂-Ph 767 MeN(CH₂Ph)CH₂CH₂OMe 2,4-Me₂-Ph 768 Me NHCH(CH₂Ph)CH₂OMe 2,4-Me₂-Ph 769 MeNH-4-tetrahydropyranyl 2,4-Me₂-Ph 770 Me NH-cyclopentyl 2,4-Me₂-Ph 771Me NHCH(CH₂OMe)₂ 2-Me-4-MeO-Ph 772 Me N(CH₂CH₂OMe)₂ 2-Me-4-MeO-Ph 773 MeNHCH(Et)CH₂OMe 2-Me-4-MeO-Ph 774 Me N(Pr)CH₂CH₂CN 2-Me-4-MeO-Ph 775 MeOCH(Et)CH₂OMe 2-Me-4-MeO-Ph 776 Me NHCH(CH₂OMe)₂ 2-Br-4-MeO-Ph 777 MeN(CH₂CH₂OMe)₂ 2-Br-4-MeO-Ph 778 Me NHCH(Et)CH₂OMe 2-Br-4-MeO-Ph 779 MeN(Pr)CH₂CH₂CN 2-Br-4-MeO-Ph 780 Me OCH(Et)CH₂OMe 2-Br-4-MeO-Ph 781 MeNHCH(CH₂OMe)₂ 2-Me-4-NMe₂-Ph 782 Me N(CH₂CH₂OMe)₂ 2-Me-4-NMe₂-Ph 783 MeNHCH(Et)CH₂OMe 2-Me-4-NMe₂-Ph 784 Me N(Pr)CH₂CH₂CN 2-Me-4-NMe₂-Ph 785 MeOCH(Et)CH₂OMe 2-Me-4-NMe₂-Ph 786 Me NHCH(CH₂OMe)₂ 2-Br-4-NMe₂-Ph 787 MeN(CH₂CH₂OMe)₂ 2-Br-4-NMe₂-Ph 788 Me NHCH(Et)CH₂OMe 2-Br-4-NMe₂-Ph 789 MeN(Pr)CH₂CH₂CN 2-Br-4-NMe₂-Ph 790 Me OCH(Et)CH₂OMe 2-Br-4-NMe₂-Ph 791 MeNHCH(CH₂OMe)₂ 2-Br-4-i-Pr-Ph 792 Me N(CH₂CH₂OMe)₂ 2-Br-4-i-Pr-Ph 793 MeNHCH(Et)CH₂OMe 2-Br-4-i-Pr-Ph 794 Me N(Pr)CH₂CH₂CN 2-Br-4-i-Pr-Ph 795 MeOCH(Et)CH₂OMe 2-Br-4-i-Pr-Ph 796 Me NHCH(CH₂OMe)₂ 2-Br-4-Me-Ph 797 MeN(CH₂CH₂OMe)₂ 2-Br-4-Me-Ph 798 Me NHCH(Et)CH₂OMe 2-Br-4-Me-Ph 799 MeN(Pr)CH₂CH₂CN 2-Br-4-Me-Ph 800 Me OCH(Et)CH₂OMe 2-Br-4-Me-Ph 801 MeNHCH(CH₂OMe)₂ 2-Me-4-Br-Ph 802 Me N(CH₂CH₂OMe)₂ 2-Me-4-Br-Ph 803 MeNHCH(Et)CH₂OMe 2-Me-4-Br-Ph 804 Me N(Pr)CH₂CH₂CN 2-Me-4-Br-Ph 805 MeOCH(Et)CH₂OMe 2-Me-4-Br-Ph 806 Me NHCH(CH₂OMe)₂ 2-Cl-4,6-Me₂-Ph 807 MeN(CH₂CH₂OMe)₂ 2-Cl-4,6-Me₂-Ph 808 Me NHCH(CH₂OMe)₂ 4-Br-2,6-(Me)₂-Ph 809Me N(CH₂CH₂OMe)₂ 4-Br-2,6-(Me)₂-Ph 810 Me NHCH(CH₂OMe)₂ 4-i-Pr-2-SMe-Ph811 Me N(CH₂CH₂OMe)₂ 4-i-Pr-2-SMe-Ph 812 Me NHCH(CH₂OMe)₂ 2-Br-4-CF₃-Ph813 Me N(CH₂CH₂OMe)₂ 2-Br-4-CF₃-Ph 814 Me NHCH(CH₂OMe)₂2-Br-4,6-(MeO)₂-Ph 815 Me N(CH₂CH₂OMe)₂ 2-Br-4,6-(MeO)₂-Ph 816 MeNHCH(CH₂OMe)₂ 2-Cl-4,6-(MeO)₂-Ph 817 Me N(CH₂CH₂OMe)₂ 2-Cl-4,6-(MeO)₂-Ph818 Me NHCH(CH₂OMe)₂ 2,6-(Me)₂-4- SMe-Ph 819 Me N(CH₂CH₂OMe)₂2,6-(Me)₂-4- SMe-Ph 820 Me NHCH(CH₂OMe)₂ 4-(COMe)-2-Br-Ph 821 MeN(CH₂CH₂OMe)₂ 4-(COMe)-2-Br-Ph 822 Me NHCH(CH₂OMe)₂ 2,4,6-Me₃-pyrid-3-yl 823 Me N(CH₂CH₂OMe)₂ 2,4,6-Me₃- pyrid-3-yl 824 MeNHCH(CH₂OMe)₂ 2,4-(Br)₂-Ph 825 Me N(CH₂CH₂OMe)₂ 2,4-(Br)₂-Ph 826 MeNHCH(CH₂OMe)₂ 4-i-Pr-2-SMe-Ph 827 Me N(CH₂CH₂OMe)₂ 4-i-Pr-2-SMe-Ph 828Me NHCH(CH₂OMe)₂ 4-i-Pr-2-SO₂Me-Ph 829 Me N(CH₂CH₂OMe)₂4-i-Pr-2-SO₂Me-Ph 830 Me NHCH(CH₂OMe)₂ 2,6-(Me)₂- 4-SMe-Ph 831 MeN(CH₂CH₂OMe)₂ 2,6-(Me)₂- 4-SMe-Ph 832 Me NHCH(CH₂OMe)₂ 2,6-(Me)₂-4-SO₂Me-Ph 833 Me N(CH₂CH₂OMe)₂ 2,6-(Me)₂- 4-SO₂Me-Ph 834 MeNHCH(CH₂OMe)₂ 2-I-4-i-Pr-Ph 835 Me N(CH₂CH₂OMe)₂ 2-I-4-i-Pr-Ph 836 MeNHCH(CH₂OMe)₂ 2-Br-4-N(Me)₂-6- MeO-Ph 837 Me N(CH₂CH₂OMe)₂2-Br-4-N(Me)₂-6- MeO-Ph 838 Me NEt₂ 2-Br-4-MeO-Ph 839 Me NH-3-pentyl2-Br-4-MeO-Ph 840 Me NHCH(CH₂OMe)₂ 2-CN-4-Me-Ph 841 Me N(c-C₃H₅)CH₂CH₂CN2,4,6-Me₃-Ph 842 Me NHCH(CH₂CH₂OMe)CH₂OMe 2-Me-4-Br-Ph 843 MeNHCH(CH₂OMe)₂ 2,5-Me₂-4-MeO-Ph 844 Me N(CH₂CH₂OMe)₂ 2,5-Me₂-4-MeO-Ph 845Me NH-3-pentyl 2,5-Me₂-4-MeO-Ph 846 Me NEt₂ 2,5-Me₂-4-MeO-Ph 847 MeNHCH(CH₂OMe)₂ 2-Cl-4-MePh 848 Me NCH(Et)CH₂OMe 2-Cl-4-MePh 849 MeN(CH₂CH₂OMe)₂ 2-Cl-4-MePh 850 Me (S)—NHCH(CH₂CH₂OMe)CH₂OMe 2-Cl-4-MePh851 Me N(c-C₃H₅)CH₂CH₂CN 2,5-Me₂-4-MeOPh 852 Me NEt₂ 2-Me-4-MeOPh 853 MeOEt 2-Me-4-MeOPh 854 Me (S)—NHCH(CH₂CH₂OMe)CH₂OMe 2-Me-4-MeOPh 855 MeN(c-C₃H₅)CH₂CH₂CN 2-Me-4-MeOPh 856 Me NHCH(CH₂CH₂OEt)₂ 2-Me-4-MeOPh 857Me N(c-C₃H₅)CH₂CH₂CN 2,4-Cl₂-Ph 858 Me NEt₂ 2-Me-4-ClPh 859 MeNH-3-pentyl 2-Me-4-ClPh 860 Me N(CH₂CH₂OMe)₂ 2-Me-4-ClPh 861 MeNHCH(CH₂OMe)₂ 2-Me-4-ClPh 862 Me NEt₂ 2-Me-4-ClPh 863 Me NEt₂2-Cl-4-MePh 864 Me NH-3-pentyl 2-Cl-4-MePh 865 Me NHCH(CH₂OMe)₂2-Cl-4-MeOPh 866 Me N(CH₂CH₂OMe)₂ 2-Cl-4-MeOPh 867 Me NHCH(Et)CH₂OMe2-Cl-4-MeOPh 868 Me N(c-Pr)CH₂CH₂CN 2-Cl-4-MeOPh 869 Me NEt₂2-Cl-4-MeOPh 870 Me NH-3-pentyl 2-Cl-4-MeOPh 871 Me NHCH(Et)CH₂CH₂OMe2-Cl-4-MeOPh 872 Me NHCH(Me)CH₂CH₂OMe 2-Cl-4-MeOPh 873 MeNHCH(Et)CH₂CH₂OMe 2-Br-4-MeOPh 874 Me NHCH(Me)CH₂CH₂OMe 2-Br-4-MeOPh 875Me NHCH(Et)CH₂CH₂OMe 2-Me-4-MeOPh 876 Me NHCH(Me)CH₂CH₂OMe 2-Me-4-MeOPh877 Me NHCH(CH₂OMe)₂ 2-Cl-4,5-(MeO)₂Ph 878 Me N(CH₂CH₂OMe)₂2-Cl-4,5-(MeO)₂Ph 879 Me NHCH(Et)CH₂OMe 2-Cl-4,5-(MeO)₂Ph 880 MeN(c-Pr)CH₂CH₂CN 2-Cl-4,5-(MeO)₂Ph 881 Me NEt₂ 2-Cl-4,5-(MeO)₂Ph 882 MeNH-3-pentyl 2-Cl-4,5-(MeO)₂Ph 883 Me NHCH(Et)CH₂CH₂OMe 2-Cl-4,5-(MeO)₂Ph884 Me NHCH(Me)CH₂CH₂OMe 2-Cl-4,5-(MeO)₂Ph 885 Me NHCH(CH₂OMe)₂2-Br-4,5-(MeO)₂Ph 886 Me N(CH₂CH₂OMe)₂ 2-Br-4,5-(MeO)₂Ph 887 MeNHCH(Et)CH₂OMe 2-Br-4,5-(MeO)₂Ph 888 Me N(c-Pr)CH₂CH₂CN2-Br-4,5-(MeO)₂Ph 889 Me NEt₂ 2-Br-4,5-(MeO)₂Ph 890 Me NH-3-pentyl2-Br-4,5-(MeO)₂Ph 891 Me NHCH(CH₂OMe)₂ 2-Cl-4,6-(MeO)₂Ph 892 MeN(CH₂CH₂OMe)₂ 2-Cl-4,6-(MeO)₂Ph 893 Me NEt₂ 2-Cl-4,6-(MeO)₂Ph 894 MeNH-3-pentyl 2-Cl-4,6-(MeO)₂Ph 895 Me NHCH(CH₂OMe)₂ 2-Me-4,6-(MeO)₂Ph 896Me N(CH₂CH₂OMe)₂ 2-Me-4,6-(MeO)₂Ph 897 Me NHCH(Et)CH₂OMe2-Me-4,6-(MeO)₂Ph 898 Me NEt₂ 2-Me-4,6-(MeO)₂Ph 899 Me NH-3-pentyl 2Me-4,6-(MeO)₂Ph 900 Me NHCH(Et)CH₂CH₂OMe 2-Me-4-MeOPh 901 MeNHCH(Me)CH₂CH₂OMe 2-Me-4-MeOPh 902 Me NHCH(CH₂OMe)₂ 2-MeO-4-MePh 903 MeN(CH₂CH₂OMe)₂ 2-MeO-4-MePh 904 Me NHCH(Et)CH₂OMe 2-MeO-4-MePh 905 MeN(c-Pr)CH₂CH₂CN 2-MeO-4-MePh 906 Me NEt₂ 2-MeO-4-MePh 907 Me NH-3-pentyl2-MeO-4-MePh 908 Me NHCH(Et)CH₂CH₂OMe 2-MeO-4-MePh 909 MeNHCH(Me)CH₂CH₂OMe 2-MeO-4-MePh 910 Me NHCH(CH₂OMe)₂ 2-MeO-4-MePh 911 MeN(CH₂CH₂OMe)₂ 2-MeO-4-MePh 912 Me NHCH(Et)CH₂OMe 2-MeO-4-MePh 913 MeN(c-Pr)CH₂CH₂CN 2-MeO-4-MePh 914 Me NEt₂ 2-MeO-4-MePh 915 Me NH-3-pentyl2-MeO-4-MePh 916 Me NHCH(CH₂OMe)₂ 2-MeO-4-ClPh 917 Me N(CH₂CH₂OMe)₂2-MeO-4-ClPh 918 Me NHCH(Et)CH₂OMe 2-MeO-4-ClPh 919 Me NEt₂ 2-MeO-4-ClPh920 Me NH-3-pentyl 2-MeO-4-ClPh

TABLE 6

Ex. R₁₄ R₃ Ar 921 Me NHCH(CH₂OMe)₂ 2,4-Cl₂-Ph 922 Me NHCHPr₂ 2,4-Cl₂-Ph923 Me NEtBU 2,4-Cl₂-Ph 924 Me NPr(CH₂-c-C₃H₅) 2,4-Cl₂-Ph 925 MeN(CH₂CH₂OMe)₂ 2,4-Cl₂-Ph 926 Me NH-3-heptyl 2,4-Cl₂-Ph 927 MeNHCH(Et)CH₂OMe 2,4-Cl₂-Ph 928 Me NEt₂ 2,4-Cl₂-Ph 929 Me NHCH(CH₂OEt)₂2,4-Cl₂-Ph 930 Me NH-3-pentyl 2,4-Cl₂-Ph 931 Me NMePh 2,4-Cl₂-Ph 932 MeNPr₂ 2,4-Cl₂-Ph 933 Me NH-3-hexyl 2,4-Cl₂-Ph 934 Me morpholino2,4-Cl₂-Ph 935 Me N(CH₂Ph)CH₂CH₂OMe 2,4-Cl₂-Ph 936 Me NHCH(CH₂Ph)CH₂OMe2,4-Cl₂-Ph 937 Me NH-4-tetrahydropyranyl 2,4-Cl₂-Ph 938 MeNH-cyclopentyl 2,4-Cl₂-Ph 939 Me OEt 2,4-Cl₂-Ph 940 Me OCH(Et)CH₂OMe2,4-Cl₂-Ph 941 Me OCH₂Ph 2,4-Cl₂-Ph 942 Me O-3-pentyl 2,4-Cl₂-Ph 943 MeSEt 2,4-Cl₂-Ph 944 Me S(O)Et 2,4-Cl₂-Ph 945 Me SO₂Et 2,4-Cl₂-Ph 946 MePh 2,4-Cl₂-Ph 947 Me 2-CF₃-Ph 2,4-Cl₂-Ph 948 Me 2-Ph-Ph 2,4-Cl₂-Ph 949Me 3-pentyl 2,4-Cl₂-Ph 950 Me cyclobutyl 2,4-Cl₂-Ph 951 Me 3-pyridyl2,4-Cl₂-Ph 952 Me CH(Et)CH₂CONMe₂ 2,4-Cl₂-Ph 953 Me CH(Et)CH₂CH₂NMe₂2,4-Cl₂-Ph 954 Me NHCH(CH₂OMe)₂ 2,4,6-Me₃-Ph 955 Me NHCHPr₂ 2,4,6-Me₃-Ph956 Me NEtBu 2,4,6-Me₃-Ph 957 Me NPr(CH₂-c-C₃H₅) 2,4,6-Me₃-Ph 958 MeN(CH₂CH₂OMe)₂ 2,4,6-Me₃-Ph 959 Me NH-3-heptyl 2,4,6-Me₃-Ph 960 MeNHCH(Et)CH₂OMe 2,4,6-Me₃-Ph 961 Me NEt₂ 2,4,6-Me₃-Ph 962 MeNHCH(CH₂OEt)₂ 2,4,6-Me₃-Ph 963 Me NH-3-pentyl 2,4,6-Me₃-Ph 964 Me NMePh2,4,6-Me₃-Ph 965 Me NPr₂ 2,4,6-Me₃-Ph 966 Me NH-3-hexyl 2,4,6-Me₃-Ph 967Me morpholino 2,4,6-Me₃-Ph 968 Me N(CH₂Ph)CH₂CH₂OMe 2,4,6-Me₃-Ph 969 MeNHCH(CH₂Ph)CH₂OMe 2,4,6-Me₃-Ph 970 Me NH-4-tetrahydropyranyl2,4,6-Me₃-Ph 971 Me NH-cyclopentyl 2,4,6-Me₃-Ph 972 Me OEt 2,4,6-Me₃-Ph973 Me OCH(Et)CH₂OMe 2,4,6-Me₃-Ph 974 Me OCH₂Ph 2,4,6-Me₃-Ph 975 MeO-3-pentyl 2,4,6-Me₃-Ph 976 Me SEt 2,4,6-Me₃-Ph 977 Me S(O)Et2,4,6-Me₃-Ph 978 Me SO₂Et 2,4,6-Me₃-Ph 979 Me CH(CO₂Et)₂ 2,4,6-Me₃-Ph980 Me C(Et)(CO₂Et)₂ 2,4,6-Me₃-Ph 981 Me CH(Et)CH₂OH 2,4,6-Me₃-Ph 982 MeCH(Et)CH₂OMe 2,4,6-Me₃-Ph 983 Me CONMe₂ 2,4,6-Me₃-Ph 984 Me COCH₃2,4,6-Me₃-Ph 985 Me CH(OH)CH₃ 2,4,6-Me₃-Ph 986 Me C(OH)Ph-3-pyridyl2,4,6-Me₃-Ph 987 Me Ph 2,4,6-Me₃-Ph 988 Me 2-Ph-Ph 2,4,6-Me₃-Ph 989 Me3-pentyl 2,4,6-Me₃-Ph 990 Me cyclobutyl 2,4,6-Me₃-Ph 991 Me 3-pyridyl2,4,6-Me₃-Ph 992 Me CH(Et)CH₂CONMe₂ 2,4,6-Me₃-Ph 993 Me CH(Et)CH₂CH₂NMe₂2,4,6-Me₃-Ph 994 Me NHCH(CH₂OMe)₂ 2,4-Me₂-Ph 995 Me N(CH₂CH₂OMe)₂2,4-Me₂-Ph 996 Me NHCH(Et)CH₂OMe 2,4-Me₂-Ph 997 Me NH-3-pentyl2,4-Me₂-Ph 998 Me NEt₂ 2,4-Me₂-Ph 999 Me N(CH₂CN)₂ 2,4-Me₂-Ph 1000 MeNHCH(Me)CH₂OMe 2,4-Me₂-Ph 1001 Me OCH(Et)CH₂OMe 2,4-Me₂-Ph 1002 MeNPr-c-C₃H₅ 2,4-Me₂-Ph 1003 Me NHCH(Me)CH₂NMe₂ 2,4-Me₂-Ph 1004 MeN(c-C₃H₅)CH₂CH₂CN 2,4-Me₂-Ph 1005 Me N(Pr)CH₂CH₂CN 2,4-Me₂-Ph 1006 MeN(Bu)CH₂CH₂CN 2,4-Me₂-Ph 1007 Me NHCHPr₂ 2,4-Me₂-Ph 1008 Me NEtBu2,4-Me₂-Ph 1009 Me NPr(CH₂-c-C₃H₅) 2,4-Me₂-Ph 1010 Me NH-3-heptyl2,4-Me₂-Ph 1011 Me NEt₂ 2,4-Me₂-Ph 1012 Me NHCH(CH₂OEt)₂ 2,4-Me₂-Ph 1013Me NH-3-pentyl 2,4-Me₂-Ph 1014 Me NMePh 2,4-Me₂-Ph 1015 Me NPr₂2,4-Me₂-Ph 1016 Me NH-3-hexyl 2,4-Me₂-Ph 1017 Me morpholino 2,4-Me₂-Ph1018 Me N(CH₂Ph)CH₂CH₂OMe 2,4-Me₂-Ph 1019 Me NHCH(CH₂Ph)CH₂OMe2,4-Me₂-Ph 1020 Me NH-4-tetrahydropyranyl 2,4-Me₂-Ph 1021 MeNH-cyclopentyl 2,4-Me₂-Ph 1022 Me NHCH(CH₂OMe)₂ 2-Me-4-MeO-Ph 1023 MeN(CH₂CH₂OMe)₂ 2-Me-4-MeO-Ph 1024 Me NHCH(Et)CH₂OMe 2-Me-4-MeO-Ph 1025 MeN(Pr)CH₂CH₂CN 2-Me-4-MeO-Ph 1026 Me OCH(Et)CH₂OMe 2-Me-4-MeO-Ph 1027 MeNHCH(CH₂OMe)₂ 2-Br-4-MeO-Ph 1028 Me N(CH₂CH₂OMe)₂ 2-Br-4-MeO-Ph 1029 MeNHCH(Et)CH₂OMe 2-Br-4-MeO-Ph 1030 Me N(Pr)CH₂CH₂CN 2-Br-4-MeO-Ph 1031 MeOCH(Et)CH₂OMe 2-Br-4-MeO-Ph 1032 Me NHCH(CH₂OMe)₂ 2-Me-4-NMe₂-Ph 1033 MeN(CH₂CH₂OMe)₂ 2-Me-4-NMe₂-Ph 1034 Me NHCH(Et)CH₂OMe 2-Me-4-NMe₂-Ph 1035Me N(Pr)CH₂CH₂CN 2-Me-4-NMe₂-Ph 1036 Me OCH(Et)CH₂OMe 2-Me-4-NMe₂-Ph1037 Me NHCH(CH₂OMe)₂ 2-Br-4-NMe₂-Ph 1038 Me N(CH₂CH₂OMe)₂2-Br-4-NMe₂-Ph 1039 Me NHCH(Et)CH₂OMe 2-Br-4-NMe₂-Ph 1040 MeN(Pr)CH₂CH₂CN 2-Br-4-NMe₂-Ph 1041 Me OCH(Et)CH₂OMe 2-Br-4-NMe₂-Ph 1042Me NHCH(CH₂OMe)₂ 2-Br-4-i-Pr-Ph 1043 Me N(CH₂CH₂OMe)₂ 2-Br-4-i-Pr-Ph1044 Me NHCH(Et)CH₂OMe 2-Br-4-i-Pr-Ph 1045 Me N(Pr)CH₂CH₂CN2-Br-4-i-Pr-Ph 1046 Me OCH(Et)CH₂OMe 2-Br-4-i-Pr-Ph 1047 MeNHCH(CH₂OMe)₂ 2-Br-4-Me-Ph 1048 Me N(CH₂CH₂OMe)₂ 2-Br-4-Me-Ph 1049 MeNHCH(Et)CH₂OMe 2-Br-4-Me-Ph 1050 Me N(Pr)CH₂CH₂CN 2-Br-4-Me-Ph 1051 MeOCH(Et)CH₂OMe 2-Br-4-Me-Ph 1052 Me NHCH(CH₂OMe)₂ 2-Me-4-Br-Ph 1053 MeN(CH₂CH₂OMe)₂ 2-Me-4-Br-Ph 1054 Me NHCH(Et)CH₂OMe 2-Me-4-Br-Ph 1055 MeN(Pr)CH₂CH₂CN 2-Me-4-Br-Ph 1056 Me OCH(Et)CH₂OMe 2-Me-4-Br-Ph 1057 MeNHCH(CH₂OMe)₂ 2-Cl-4,6-Me₂-Ph 1058 Me N(CH₂CH₂OMe)₂ 2-Cl-4,6-Me₂-Ph 1059Me NHCH(CH₂OMe)₂ 4-Br-2,6-(Me)₂-Ph 1060 Me N(CH₂CH₂OMe)₂4-Br-2,6-(Me)₂-Ph 1061 Me NHCH(CH₂OMe)₂ 4-i-Pr-2-SMe-Ph 1062 MeN(CH₂CH₂OMe)₂ 4-i-Pr-2-SMe-Ph 1063 Me NHCH(CH₂OMe)₂ 2-Br-4-CF₃-Ph 1064Me N(CH₂CH₂OMe)₂ 2-Br-4-CF₃-Ph 1065 Me NHCH(CH₂OMe)₂ 2-Br-4,6-(MeO)₂-Ph1066 Me N(CH₂CH₂OMe)₂ 2-Br-4,6-(MeO)₂-Ph 1067 Me NHCH(CH₂OMe)₂2-Cl-4,6-(MeO)₂-Ph 1068 Me N(CH₂CH₂OMe)₂ 2-Cl-4,6-(MeO)₂-Ph 1069 MeNHCH(CH₂OMe)₂ 2,6-(Me)₂-4- SMe-Ph 1070 Me N(CH₂CH₂OMe)₂ 2,6-(Me)₂-4-SMe-Ph 1071 Me NHCH(CH₂OMe)₂ 4-(COMe)-2-Br-Ph 1072 Me N(CH₂CH₂OMe)₂4-(COMe)-2-Br-Ph 1073 Me NHCH(CH₂OMe)₂ 2,4,6-Me₃- pyrid-3-yl 1074 MeN(CH₂CH₂OMe)₂ 2,4,6-Me₃- pyrid-3-yl 1075 Me NHCH(CH₂OMe)₂ 2,4-(Br)₂-Ph1076 Me N(CH₂CH₂OMe)₂ 2,4-(Br)₂-Ph 1077 Me NHCH(CH₂OMe)₂ 4-i-Pr-2-SMe-Ph1078 Me N(CH₂CH₂OMe)₂ 4-i-Pr-2-SMe-Ph 1079 Me NHCH(CH₂OMe)₂4-i-Pr-2-SO₂Me-Ph 1080 Me N(CH₂CH₂OMe)₂ 4-i-Pr-2-SO₂Me-Ph 1081 MeNHCH(CH₂OMe)₂ 2,6-(Me)₂-4- SMe-Ph 1082 Me N(CH₂CH₂OMe)₂ 2,6-(Me)₂-4-SMe-Ph 1083 Me NHCH(CH₂OMe)₂ 2,6-(Me)₂-4- SO₂Me-Ph 1084 Me N(CH₂CH₂OMe)₂2,6-(Me)₂-4- SO₂Me-Ph 1085 Me NHCH(CH₂OMe)₂ 2-I-4-i-Pr-Ph 1086 MeN(CH₂CH₂OMe)₂ 2-I-4-i-Pr-Ph 1087 Me NHCH(CH₂OMe)₂ 2-Br-4-N(Me)₂-6-MeO-Ph 1088 Me N(CH₂CH₂OMe)₂ 2-Br-4-N(Me)₂- 6-MeO-Ph 1089 Me NEt₂2-Br-4-MeO-Ph 1090 Me NH-3-pentyl 2-Br-4-MeO-Ph 1091 Me NHCH(CH₂OMe)₂2-CN-4-Me-Ph 1092 Me N(c-C₃H₅)CH₂CH₂CN 2,4,6-Me₃-Ph 1093 MeNHCH(CH₂CH₂OMe)CH₂OMe 2-Me-4-Br-Ph 1094 Me NHCH(CH₂OMe)₂2,5-Me₂-4-MeO-Ph 1095 Me N(CH₂CH₂OMe)₂ 2,5-Me₂-4-MeO-Ph 1096 MeNH-3-pentyl 2,5-Me₂-4-MeO-Ph 1097 Me NEt₂ 2,5-Me₂-4-MeO-Ph 1098 MeNHCH(CH₂OMe)₂ 2-Cl-4-MePh 1099 Me NCH(Et)CH₂OMe 2-Cl-4-MePh 1100 MeN(CH₂CH₂OMe)₂ 2-Cl-4-MePh 1101 Me (S)—NHCH(CH₂CH₂OMe)CH₂OMe 2-Cl-4-MePh1102 Me N(c-C₃H₅)CH₂CH₂CN 2,5-Me₂-4-MeOPh 1103 Me NEt₂ 2-Me-4-MeOPh 1104Me OEt 2-Me-4-MeOPh 1105 Me (S)—NHCH(CH₂CH₂OMe)CH₂OMe 2-Me-4-MeOPh 1106Me N(c-C₃H₅)CH₂CH₂CN 2-Me-4-MeOPh 1107 Me NHCH(CH₂CH₂OEt)₂ 2-Me-4-MeOPh1108 Me N(c-C₃H₅)CH₂CH₂CN 2,4-Cl₂-Ph 1109 Me NEt₂ 2-Me-4-ClPh 1110 MeNH-3-pentyl 2-Me-4-ClPh 1111 Me N(CH₂CH₂OMe)₂ 2-Me-4-ClPh 1112 MeNHCH(CH₂OMe)₂ 2-Me-4-ClPh 1113 Me NEt₂ 2-Me-4-ClPh 1114 Me NEt₂2-Cl-4-MePh 1115 Me NH-3-pentyl 2-Cl-4-MePh 1116 Me NHCH(CH₂OMe)₂2-Cl-4-MeOPh 1117 Me N(CH₂CH₂OMe)₂ 2-Cl-4-MeOPh 1118 Me NHCH(Et)CH₂OMe2-Cl-4-MeOPh 1119 Me N(c-Pr)CH₂CH₂CN 2-Cl-4-MeOPh 1120 Me NEt₂2-Cl-4-MeOPh 1121 Me NH-3-pentyl 2-Cl-4-MeOPh 1123 Me NHCH(Et)CH₂CH₂OMe2-Cl-4-MeOPh 1124 Me NHCH(Me)CH₂CH₂OMe 2-Cl-4-MeOPh 1125 MeNHCH(Et)CH₂CH₂OMe 2-Br-4-MeOPh 1126 Me NHCH(Me)CH₂CH₂OMe 2-Br-4-MeOPh1127 Me NHCH(Et)CH₂CH₂OMe 2-Me-4-MeOPh 1128 Me NHCH(Me)CH₂CH₂OMe2-Me-4-MeOPh 1129 Me NHCH(CH₂OMe)₂ 2-Cl-4,5-(MeO)₂Ph 1130 MeN(CH₂CH₂OMe)₂ 2-Cl-4,5-(MeO)₂Ph 1131 Me NHCH(Et)CH₂OMe 2-Cl-4,5-(MeO)₂Ph1132 Me N(c-Pr)CH₂CH₂CN 2-Cr-4,5-(Meo)₂Ph 1133 Me NEt₂ 2-Cl-4,5-(MeO)₂Ph1134 Me NH-3-pentyl 2-Cl-4,5-(MeO)₂Ph 1135 Me NHCH(Et)CH₂CH₂OMe2-Cl-4,5-(MeO)₂Ph 1136 Me NHCH(Me)CH₂CH₂OMe 2-Cl-4,5-(MeO)₂Ph 1137 MeNHCH(CH₂OMe)₂ 2-Br-4,5-(MeO)₂Ph 1138 Me N(CH₂CH₂OMe)₂ 2-Br-4,5-(MeO)₂Ph1139 Me NHCH(Et)CH₂OMe 2-Br-4,5-(Meo)₂Ph 1140 Me N(c-Pr)CH₂CH₂CN2-Br-4,5-(MeO)₂Ph 1141 Me NEt₂ 2-Br-4,5-(MeO)₂Ph 1142 Me NH-3-pentyl2-Br-4,5-(MeO)₂Ph 1143 Me NHCH(CH₂OMe)₂ 2-Cl-4,6-(MeO)₂Ph 1144 MeN(CH₂CH₂OMe)₂ 2-Cl-4,6-(MeO)₂Ph 1145 Me NEt₂ 2-Cl-4,6-(MeO)₂Ph 1146 MeNH-3-pentyl 2-Cl-4,6-(MeO)₂Ph 1147 Me NHCH(CH₂OMe)₂ 2-Me-4,6-(MeO)₂Ph1148 Me N(CH₂CH₂OMe)₂ 2-Me-4,6-(MeO)₂Ph 1149 Me NHCH(Et)CH₂OMe2-Me-4,6-(MeO)₂Ph 1150 Me NEt₂ 2-Me-4,6-(MeO)₂Ph 1151 Me NH-3-pentyl2-Me-4,6-(MeO)₂Ph 1152 Me NHCH(Et)CH₂CH₂OMe 2-Me-4-MeOPh 1153 MeNHCH(Me)CH₂CH₂OMe 2-Me-4-MeOPh 1154 Me NHCH(CH₂OMe)₂ 2-MeO-4-MePh 1155Me N(CH₂CH₂OMe)₂ 2-MeO-4-MePh 1156 Me NHCH(Et)CH₂OMe 2-MeO-4-MePh 1157Me N(c-Pr)CH₂CH₂CN 2-MeO-4-MePh 1158 Me NEt₂ 2-MeO-4-MePh 1159 MeNH-3-pentyl 2-MeO-4-MePh 1160 Me NHCH(Et)CH₂CH₂OMe 2-MeO-4-MePh 1161 MeNHCH(Me)CH₂CH₂OMe 2-MeO-4-MePh 1162 Me NHCH(CH₂OMe)₂ 2-MeO-4-MePh 1163Me N(CH₂CH₂OMe)₂ 2-MeO-4-MePh 1164 Me NHCH(Et)CH₂OMe 2-MeO-4-MePh 1165Me N(c-Pr)CH₂CH₂CN 2-MeO-4-MePh 1166 Me NEt₂ 2-MeO-4-MePh 1167 MeNH-3-pentyl 2-MeO-4-MePh 1168 Me NHCH(CH₂OMe)₂ 2-MeO-4-ClPh 1169 MeN(CH₂CH₂OMe)₂ 2-MeO-4-ClPh 1170 Me NHCH(Et)CH₂OMe 2-MeO-4-ClPh 1171 MeNEt₂ 2-MeO-4-ClPh 1172 Me NH-3-pentyl 2-MeO-4-ClPh

Utility CRF-R1 Receptor Binding Assay for the Evaluation of BiologicalActivity

The following is a description of the isolation of cell membranescontaining cloned human CRF-R1 receptors for use in the standard bindingassay as well as a description of the assay itself.

Messenger RNA was isolated from human hippocampus. The mRNA was reversetranscribed using oligo (dt) 12-18 and the coding region was amplifiedby PCR from start to stop codons. The resulting PCR fragment was clonedinto the EcoRV site of pGEMV, from whence the insert was reclaimed usingXhoI+XbaI and cloned into the XhoI+XbaI sites of vector pm3ar (whichcontains a CMV promoter, the SV40 ‘t’ splice and early poly A signals,an Epstein-Barr viral origin of replication, and a hygromycin selectablemarker). The resulting expression vector, called phchCRFR wastransfected in 293EBNA cells and cells retaining the episome wereselected in the presence of 400 μM hygromycin. Cells surviving 4 weeksof selection in hygromycin were pooled, adapted to growth in suspensionand used to generate membranes for the binding assay described below.Individual aliquots containing approximately 1×10⁸ of the suspendedcells were then centrifuged to form a pellet and frozen.

For the binding assay a frozen pellet described above containing 293EBNAcells transfected with hCRFR1 receptors is homogenized in 10 ml of icecold tissue buffer (50 mM HEPES buffer pH 7.0, containing 10 mM MgCl₂, 2mM EGTA, 1 μg/l aprotinin, 1 μg/ml leupeptin and 1 μg/ml pepstatin). Thehomogenate is centrifuged at 40,000×g for 12 min and the resultingpellet rehomogenized in 10 ml of tissue buffer. After anothercentrifugation at 40,000×g for 12 min, the pellet is resuspended to aprotein concentration of 360 μg/ml to be used in the assay.

Binding assays are performed in 96 well plates; each well having a 300μl capacity. To each well is added 50 μl of test drug dilutions (finalconcentration of drugs range from 10−¹⁰ -10−⁵ M), 100 μl of¹²⁵I-ovine-CRF (¹²⁵I-o-CRF) (final concentration 150 pM) and 150 μl ofthe cell homogenate described above. Plates are then allowed to incubateat room temperature for 2 hours before filtering the incubate over GF/Ffilters (presoaked with 0.3% polyethyleneimine) using an appropriatecell harvester. Filters are rinsed 2 times with ice cold assay bufferbefore removing individual filters and assessing them for radioactivityon a gamma counter.

Curves of the inhibition of ¹²⁵I-o-CRF binding to cell membranes atvarious dilutions of test drug are analyzed by the iterative curvefitting program LIGAND [P. J. Munson and D. Rodbard, Anal. Biochem.107:220 (1980), which provides Ki values for inhibition which are thenused to assess biological activity.

A compound is considered to be active if it has a K_(i) value of lessthan about 10000 nM for the inhibition of CRF.

Inhibition of CRF-Stimulated Adenylate Cyclase Activity

Inhibition of CRF-stimulated adenylate cyclase activity can be performedas described by G. Battaglia et al. Synapse 1:572 (1987). Briefly,assays are carried out at 37° C. for 10 min in 200 ml of buffercontaining 100 mM Tris-HCl (pH 7.4 at 37° C.), 10 mM MgCl₂, 0.4 mM EGTA,0.1% BSA, 1 mM isobutylmethylxanthine (IBMX), 250 units/mlphosphocreatine kinase, 5 mM creatine phosphate, 100 mM guanosine5′-triphosphate, 100 nM oCRF, antagonist peptides (concentration range10⁻⁹ to 10^(−6m)) and 0.8 mg original wet weight tissue (approximately40-60 mg protein). Reactions are initiated by the addition of 1 mMATP/³²P]ATP (approximately 2-4 mCi/tube) and terminated by the additionof 100 ml of 50 mM Tris-HCl, 45 mM ATP and 2% sodium dodecyl sulfate. Inorder to monitor the recovery of cAMP, 1 μl of [³H]cAMP (approximately40,000 dpm) is added to each tube prior to separation. The separation of[³²P]cAMP from [³²P]ATP is performed by sequential elution over Dowexand alumina columns.

In vivo Biological Assay

The in vivo activity of the compounds of the present invention can beassessed using any one of the biological assays available and acceptedwithin the art. Illustrative of these tests include the Acoustic StartleAssay, the Stair Climbing Test, and the Chronic Administration Assay.These and other models useful for the testing of compounds of thepresent invention have been outlined in C. W. Berridge and A. J. DunnBrain Research Reviews 15:71 (1990). Compounds may be tested in anyspecies of rodent or small mammal.

Compounds of this invention have utility in the treatment of imbalancesassociated with abnormal levels of corticotropin releasing factor inpatients suffering from depression, affective disorders, and/or anxiety.

Compounds of this invention can be administered to treat theseabnormalities by means that produce contact of the active agent with theagent's site of action in the body of a mammal. The compounds can beadministered by any conventional means available for use in conjunctionwith pharmaceuticals either as individual therapeutic agent or incombination of therapeutic agents. They can be administered alone, butwill generally be administered with a pharmaceutical carrier selected onthe basis of the chosen route of administration and standardpharmaceutical practice.

The dosage administered will vary depending on the use and known factorssuch as pharmacodynamic character of the particular agent, and its modeand route of administration; the recipient's age, weight, and health;nature and extent of symptoms; kind of concurrent treatment; frequencyof treatment; and desired effect. For use in the treatment of saiddiseases or conditions, the compounds of this invention can be orallyadministered daily at a dosage of the active ingredient of 0.002 to 200mg/kg of body weight. Ordinarily, a dose of 0.01 to 10 mg/kg in divideddoses one to four times a day, or in sustained release formulation willbe effective in obtaining the desired pharmacological effect.

Dosage forms (compositions) suitable for administration contain fromabout 1 mg to about 100 mg of active ingredient per unit. In thesepharmaceutical compositions, the active ingredient will ordinarily bepresent in an amount of about 0.5 to 95% by weight based on the totalweight of the composition.

The active ingredient can be administered orally is solid dosage forms,such as capsules, tablets and powders; or in liquid forms such aselixirs, syrups, and/or suspensions. The compounds of this invention canalso be administered parenterally in sterile liquid dose formulations.

Gelatin capsules can be used to contain the active ingredient and asuitable carrier such as but not limited to lactose, starch, magnesiumstearate, steric acid, or cellulose derivatives. Similar diluents can beused to make compressed tablets. Both tablets and capsules can bemanufactured as sustained release products to provide for continuousrelease of medication over a period of time. Compressed tablets can besugar-coated or film-coated to mask any unpleasant taste, or used toprotect the active ingredients from the atmosphere, or to allowselective disintegration of the tablet in the gastrointestinal tract.

Liquid dose forms for oral administration can contain coloring orflavoring agents to increase patient acceptance.

In general, water, pharmaceutically acceptable oils, saline, aqueousdextrose (glucose), and related sugar solutions and glycols, such aspropylene glycol or polyethylene glycol, are suitable carriers forparenteral solutions. Solutions for parenteral administration preferablycontain a water soluble salt of the active ingredient, suitablestabilizing agents, and if necessary, butter substances. Antioxidizingagents, such as sodium bisulfite, sodium sulfite, or ascorbic acid,either alone or in combination, are suitable stabilizing agents. Alsoused are citric acid and its salts, and EDTA. In addition, parenteralsolutions can contain preservatives such as benzalkonium chloride,methyl- or propyl-paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described in “Remington'sPharmaceutical Sciences”, A. Osol, a standard reference in the field.

Useful pharmaceutical dosage-forms for administration of the compoundsof this invention can be illustrated as follows:

Capsules

A large number of units capsules are prepared by filling standardtwo-piece hard gelatin capsules each with 100 mg of powdered activeingredient, 150 mg lactose, 50 mg cellulose, and 6 mg magnesiumstearate.

Soft Gelatin Capsules

A mixture of active ingredient in a digestible oil such as soybean,cottonseed oil, or olive oil is prepared and injected by means of apositive displacement was pumped into gelatin to form soft gelatincapsules containing 100 mg of the active ingredient. The capsules werewashed and dried.

Tablets

A large number of tablets are prepared by conventional procedures sothat the dosage unit was 100 mg active ingredient, 0.2 mg of colloidalsilicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystallinecellulose, 11 mg of starch, and 98.8 mg lactose. Appropriate coatingsmay be applied to increase palatability or delayed adsorption.

The compounds of this invention may also be used as reagents orstandards in the biochemical study of neurological function,dysfunction, and disease.

Although the present invention has been described and exemplified interms of certain preferred embodiments, other embodiments will beapparent to those skilled in the art. The invention is, therefore, notlimited to the particular embodiments described and exemplified, but iscapable of modification or variation without departing from the spiritof the invention, the full scope of which is delineated by the appendedclaims.

What is claimed is:
 1. A compound of Formula (1):

and isomers thereof, stereoisomeric forms thereof, or mixtures ofstereoisomeric forms thereof, and pharmaceutically acceptable salt formsthereof wherein: Z is CR²; Ar is selected from phenyl, naphthyl,pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, benzothienyl,benzofuranyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, indanyl,1,2-benzopyranyl, 3,4-dihydro-1,2-benzopyranyl, tetralinyl, each Aroptionally substituted with 1 to 5 R⁴ groups and each Ar is attached toan unsaturated carbon atom; R¹ is independently selected at eachoccurrence from H, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, halo, CN,C₁-C₄ haloalkyl, C₁-C₁₂ hydroxyalkyl, C₂-C₁₂ alkoxyalkyl, C₂-C₁₀cyanoalkyl, C₃-C₆ cycloalkyl, C₄-C₁₀ cycloalkylalkyl, NR⁹R¹⁰, C₁-C₄alkyl-NR⁹R¹⁰, NR⁹COR¹⁰, OR¹¹, SH or S(O)_(n)R¹²; R² is selected from H,C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆ cycloalkyl, C₄-C₁₀cycloalkylalkyl, C₁-C₄ hydroxyalkyl, halo, CN, —NR⁶R⁷, NR⁹COR¹⁰,—NR⁶S(O)_(n)R⁷, S(O)_(n)NR⁶R⁷, C₁-C₄ haloalkyl, —OR⁷, SH or—S(O)_(n)R¹²; R³ is selected from: H, SH, S(O)_(n)R¹³, COR⁷, CO₂R⁷,OC(O)R¹³, NR⁸COR⁷, N(COR⁷)₂, NR⁸CONR⁶R⁷, NR⁸CO₂R¹³, N(OR⁷)R⁶, CONR⁶R⁷,aryl, heteroaryl and heterocyclyl, or C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl,C₂-C₁₀ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, C₄-C₁₂cycloalkylalkyl or C₆-C₁₀ cycloalkenylalkyl, each optionally substitutedwith 1 to 3 substituents independently selected at each occurrence fromC₁-C₆ alkyl, C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl, cyano, OR¹⁵, SH,S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵,NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroaryl and heterocyclyl; R⁴ isindependently selected at each occurrence from: C₁-C₁₀ alkyl, C₂-C₁₀alkenyl, C₂-C₁₀ alkynyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl, NO₂,halo, CN, C₁-C₄ haloalkyl, NR⁶R⁷, NR⁸COR⁷, NR⁸CO₂R⁷, COR⁷, OR⁷, CONR⁶R⁷,CO(NOR⁹)R⁷, CO₂R⁷, or S(O)_(n)R⁷, where each such C₁-C₁₀ alkyl, C₂-C₁₀alkenyl, C₂-C₁₀ alkynyl, C₃-C₆ cycloalkyl and C₄-C₁₂ cycloalkylalkyl areoptionally substituted with 1 to 3 substituents independently selectedat each occurrence from C₁-C₄ alkyl, NO₂, halo, CN, NR⁶R⁷, NR⁸COR⁷,NR⁸CO₂R⁷, COR⁷ OR⁷, CONR⁶R⁷, CO₂R⁷, CO(NOR⁹)R⁷, or S(O)_(n)R⁷; R⁶, R7,R^(6a) and R^(7a) are independently selected at each occurrence from: H,C₁-C₁₀ alkyl, C₃-C₁₀ alkenyl, C₃-C₁₀ alkynyl, C₁-C₁₀ haloalkyl with 1-10halogens, C₂-C₈ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl,C₅-C₁₀ cycloalkenyl, or C₆-C₁₄ cycloalkenylalkyl, each optionallysubstituted with 1 to 3 substituents independently selected at eachoccurrence from C₁-C₆ alkyl, C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl,cyano, OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵,N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroarylor heterocyclyl, aryl, aryl(C₁-C₄ alkyl), heteroaryl, heteroaryl(C₁-C₄alkyl), heterocyclyl or heterocyclyl(C₁-C₄ alkyl), alternatively, NR⁶R⁷and NR^(6a)R^(7a) are independently piperidine, pyrrolidine, piperazine,N-methylpiperazine, morpholine or thiomorpholine, each optionallysubstituted with 1-3 C₁-C₄ alkyl groups; R⁸ is independently selected ateach occurrence from H or C₁-C₄ alkyl; R⁹ and R¹⁰ are independentlyselected at each occurrence from H, C₁-C₄ alkyl, or C₃-C₆ cycloalkyl;R¹¹ is selected from H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₃-C₆cycloalkyl; R¹² is C₁-C₄ alkyl or C₁-C₄ haloalkyl; R¹³ is selected fromC₁-C₄ alkyl, C₁-C₄ haloalkyl, C₂-C₈ alkoxyalkyl, C₃-C₆ cycloalkyl,C₄-C₁₂ cycloalkylalkyl, aryl, aryl(C₁-C₄ alkyl)-, heteroaryl orheteroaryl(C₁-C₄ alkyl)-; R¹⁴ is selected from C₁-C₁₀ alkyl, C₃-C₁₀alkenyl, C₃-C₁₀ alkynyl, C₃-C₈ cycloalkyl, or C₄-C₁₂ cycloalkylalkyl,each optionally substituted with 1 to 3 substituents independentlyselected at each occurrence from C₁-C₆ alkyl, C₃-C₆ cycloalkyl, halo,C₁-C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹⁵, COR¹⁵, CO₂R¹⁵, OC(O)R¹⁵,NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹⁵, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, andC₁-C₆ alkylthio, C₁-C₆ alkylsulfinyl and C₁-C₆ alkylsulfonyl; R¹⁵ andR¹⁶ are independently selected at each occurrence from H, C₁-C₆ alkyl,C₃-C₁₀ cycloalkyl, C₄-C₁₆ (cycloalkylalkyl, except that for S(O)_(n)R¹⁵,R¹⁵ cannot be H; aryl is phenyl or naphthyl, each optionally substitutedwith 1 to 5 substituents independently selected at each occurrence fromC₁-C₆ alkyl, C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl, cyano, OR¹⁵, SH,S(O)_(n)R¹⁵, COR¹⁵, CO₂R¹⁵, OC(O)R¹⁵, NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵,NR⁸CO₂R¹⁵, NR¹⁶R¹⁵, and CONR¹⁶R¹⁵; heteroaryl is pyridyl, pyrimidinyl,triazinyl, furanyl, pyranyl, quinolinyl, isoquinolinyl, thienyl,imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl,benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl,2,3-dihydrobenzothienyl or 2,3-dihydrobenzofuranyl, each beingoptionally substituted with 1 to 5 substituents independently selectedat each occurrence from C₁-C₆ alkyl, C₃-C₆ cycloalkyl, halo, C₁-C₄haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹⁵, —COR¹⁵, CO₂R¹⁵, OC(O)R¹⁵,NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹⁵, NR¹⁶R¹⁵, and CONR¹⁶R¹⁵;heterocyclyl is saturated or partially saturated heteroaryl, optionallysubstituted with 1 to 5 substituents independently selected at eachoccurrence from C₁-C₆ alkyl, C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl,cyano, OR¹⁵, SH, S(O)_(n)R¹⁵, COR¹⁵, CO₂R¹⁵, OC(O)R¹⁵, NR⁸COR¹⁵,N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹⁵, NR¹⁵R¹⁶, and CONR¹⁶R¹⁵; n isindependently at each occurrence 0, 1 or 2;  with the provisos that: (1)when R² is H and R³ is OCOR¹³ and R⁷ is H, then R¹ is not H, OH or SH;(2) when R¹ is CH₃ or C₂H₅ and R² is H, and R³ is H, CH₃, C₂H₅, C₆H₅,n-C₃H₇, i-C₃H₇, SH or SCH₃, then Ar is not phenyl or m-CH₃-phenyl; and(3) when R² is —NR⁶SO₂R⁷ or —SO₂NR⁶R⁷, then R³ is not SH.
 2. A compoundof claim 1 and isomers thereof, stereoisomeric forms thereof, ormixtures of stereoisomeric forms thereof, and pharmaceuticallyacceptable salt forms thereof wherein Ar is phenyl, pyridyl or2,3-dihydrobenzofuranyl, each optionally substituted with 1 to 4 R⁴substituents.
 3. A compound of claim 1 and isomers thereof,stereoisomeric forms thereof, or mixtures of stereoisomeric formsthereof, and pharmaceutically acceptable salt forms thereof wherein:R^(6a) is independently selected from: H, C₁-C₁₀ alkyl, C₃-C₁₀ alkenyl,C₃-C₁₀ alkynyl, C₁-C₁₀ haloalkyl with 1-10 halogens, C₂-C₈ alkoxyalkyl,C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl, C₅-C₁₀ cycloalkenyl, or C₆-C₁₄cycloalkenylalkyl, each optionally substituted with 1 to 3 substituentsindependently selected at each occurrence from C₁-C₆ alkyl, C₃-C₆cycloalkyl, halo, C₁-C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵,CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵,CONR¹⁶R¹⁵, aryl, heteroaryl or heterocyclyl, aryl, aryl(C₁-C₄ alkyl)-,heteroaryl, heteroaryl(C₁-C₄ alkyl)-, heterocyclyl or heterocyclyl(C₁-C₄alkyl)-; and R^(7a) is independently selected at each occurrence from:H, C₅-C₁₀ alkyl, C₃-C₁₀ alkenyl, C₃-C₁₀ alkynyl, C₁-C₁₀ haloalkyl with1-10 halogens, C₂-C₈ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₁₂cycloalkylalkyl, C₅-C₁₀ cycloalkenyl, or C₆-C₁₄ cycloalkenylalkyl, eachoptionally substituted with 1 to 3 substituents independently selectedat each occurrence from C₁-C₆ alkyl, C₃-C₆ cycloalkyl, halo, C₁-C₄haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³,NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl,heteroaryl or heterocyclyl, aryl, aryl(C₁-C₄ alkyl), heteroaryl,heteroaryl(C₁-C₄ alkyl), heterocyclyl or heterocyclyl(C₁-C₄ alkyl);alternatively, NR⁶R⁷ and NR^(6a)R^(7a) are independently piperidine,pyrrolidine, piperazine, N-methylpiperazine, morpholine orthiomorpholine, each optionally substituted with 1-3 C₁-C₄ alkyl groups.4. A compound of claim 1 and isomers thereof, stereoisomeric formsthereof, or mixtures of stereoisomeric forms thereof, andpharmaceutically acceptable salt forms thereof wherein: R^(6a) andR^(7a) are identical and are selected from: C₁-C₄ alkyl or C₃-C₆cycloalkyl, each optionally substituted with 1 to 3 substituentsindependently selected at each occurrence from C₁-C₆ alkyl, C₃-C₆cycloalkyl, halo, C₁-C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹³, —COR¹⁵,CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵, N(COR¹⁵)2, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵,CONR¹⁶R¹⁵, aryl, heteroaryl or heterocyclyl, and aryl or heteroaryl. 5.A compound of claim 1 and isomers thereof, stereoisomeric forms thereof,or mixtures of stereoisomeric forms thereof, and pharmaceuticallyacceptable salt forms thereof wherein: R^(6a) is selected from: H,C₁-C₁₀ alkyl, C₃-C₁₀ alkenyl, C₃-C₁₀ alkynyl, C₁-C₁₀ haloalkyl with 1-10halogens, C₂-C₈ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl,C₅-C₁₀ cycloalkenyl, or C₆-C₁₄ cycloalkenylalkyl, each optionallysubstituted with 1 to 3 substituents independently selected at eachoccurrence from C₁-C₆ alkyl, C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl,cyano, OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵,N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroarylor heterocyclyl, aryl, aryl(C₁-C₄ alkyl), heteroaryl, heteroaryl(C₁-C₄alkyl), heterocyclyl or heterocyclyl(C₁-C₄ alkyl); R^(7a) is selectedfrom: C₁-C₄ alkyl and each such C₁-C₄ alkyl is substituted with 1-3substituents independently selected at each occurrence from C₁-C₆ alkyl,C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)nR¹³,COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³,NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroaryl or heterocyclyl.
 6. A compound ofclaim 1 and isomers thereof, stereoisomeric forms thereof, or mixturesof stereoisomeric forms thereof, and pharmaceutically acceptable saltforms thereof wherein: one of R^(6a) and R^(7a) is selected from: C₃-C₆cycloalkyl, each such C₃-C₆ cycloalkyl optionally substituted with 1-3substituents independently selected at each occurrence from C₁-C₆ alkyl,C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)nR¹³,COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³,NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroaryl or heterocyclyl, aryl, heteroarylor heterocyclyl, and the other of R^(6a) and R^(7a) is unsubstitutedC₁-C₄ alkyl.
 7. A compound of claim 1 and isomers thereof,stereoisomeric forms thereof, or mixtures of stereoisomeric formsthereof, and pharmaceutically acceptable salt forms thereof whereinR^(6a) and R^(7a) are independently H or C₁-C₁₀ alkyl, each such C₁-C₁₀alkyl optionally substituted with 1 to 3 substituents independentlyselected at each occurrence from C₁-C₆ alkyl, C₃-C₆ cycloalkyl, halo,C₁-C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³,NR⁸COR¹⁵, N(COR¹⁵)₂, R⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl,heteroaryl or heterocyclyl.
 8. A compound of claim 1 and isomersthereof, stereoisomeric forms thereof, or mixtures of stereoisomericforms thereof, and pharmaceutically acceptable salt forms thereofwherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar isoptionally substituted with 1 to 4 R⁴ substituents, R¹ and R² areindependently selected from H, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, C₄-C₁₀cycloalkylalkyl; with the proviso that when Ar is phenyl orm-CH₃-phenyl, R³ is not H, CH₃, C₂H₅, C₆H₅, n-C₃H₇, i-C₃H₇, SH or SCH₃.9. A compound of claim 8 and isomers thereof, stereoisomeric formsthereof, or mixtures of stereoisomeric forms thereof, andpharmaceutically acceptable salt forms thereof wherein R^(6a) and R^(7a)are independently H or C₁-C₁₀ alkyl, each such C₁-C₁₀ alkyl optionallysubstituted with 1 to 3 substituents independently selected at eachoccurrence from C₁-C₆ alkyl, C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl,cyano, OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵,N(COR¹⁵)₂, R⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroarylor heterocyclyl.
 10. A compound of claim 1 and isomers thereof,stereoisomeric forms thereof, or mixtures of stereoisomeric formsthereof, and pharmaceutically acceptable salt forms thereof wherein R¹is independently selected at each occurrence from H, C₁-C₄ alkyl, C₂-C₄alkenyl, C₂-C₄ alkynyl, halo, CN, C₁-C₄ haloalkyl, C₁-C₁₂ hydroxyalkyl,C₂-C₁₂ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₁₀ cycloalkylalkyl.
 11. Acompound of claim 1 and isomers thereof, stereoisomeric forms thereof,or mixtures of stereoisomeric forms thereof, and pharmaceuticallyacceptable salt forms thereof wherein R² is selected from H, C₁-C₄alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆ cycloalkyl, C₄-C₁₀cycloalkylalkyl, C₁-C₄ hydroxyalkyl, halo, CN, —NR⁶R⁷, C₁-C₄ haloalkyl,—OR⁷.
 12. A compound of claim 1 and isomers thereof, stereoisomericforms thereof, or mixtures of stereoisomeric forms thereof, andpharmaceutically acceptable salt forms thereof wherein R⁴ isindependently selected at each occurrence from: C₁-C₁₀ alkyl, C₂-C₁₀alkenyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl, halo, CN, C₁-C₄haloalkyl, NR⁶R⁷, COR⁷, OR⁷, where each such C₁-C₁₀ alkyl, C₂-C₁₀alkenyl, C₂-C₃-C₆ cycloalkyl and C₄-C₁₂ cycloalkylalkyl are optionallysubstituted with 1 to 3 substituents independently selected at eachoccurrence from C₁-C₄ alkyl, NR⁶R⁷, COR⁷ OR⁷, CO₂R⁷.
 13. A compound ofclaim 1 and isomers thereof, stereoisomeric forms thereof, or mixturesof stereoisomeric forms thereof, and pharmaceutically acceptable saltforms thereof wherein R⁴ is independently selected at each occurrencefrom: H, C₁-C₁₀ alkyl, C₁-C₄ alkoxy, halo, CN and —NR⁶R⁷.
 14. Apharmaceutical composition comprising a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound of claim 1.